Pyrrole compounds, a process for their preparation and pharmaceutical

ABSTRACT

Compounds of formula (I):wherein A1, A2, Ra, Rb, Rc, Rd, R3, R4, R5 and T are as defined in the description. Medicinal products containing the same which are useful in treating pathologies involving a deficit in apoptosis, such as cancer, auto-immune diseases, and diseases of the immune system.

The present invention relates to new pyrrole compounds, to a process fortheir preparation and to pharmaceutical compositions containing them.

The compounds of the present invention are new and have very valuablepharmacological characteristics in the field of apoptosis andcancerology.

Apoptosis, or programmed cell death, is a physiological process that iscrucial for embryonic development and maintenance of tissue homeostasis.

Apoptotic-type cell death involves morphological changes such ascondensation of the nucleus, DNA fragmentation and also biochemicalphenomena such as the activation of caspases which cause damage to keystructural components of the cell, so inducing its disassembly anddeath. Regulation of the process of apoptosis is complex and involvesthe activation or repression of several intracellular signallingpathways (Cory S. et al., Nature Review Cancer, 2002, 2, 647-656).

Deregulation of apoptosis is involved in certain pathologies. Increasedapoptosis is associated with neurodegenerative diseases such asParkinson's disease, Alzheimer's disease and ischaemia. Conversely,deficits in the implementation of apoptosis play a significant role inthe development of cancers and their chemoresistance, in auto-immunediseases, inflammatory diseases and viral infections. Accordingly,absence of apoptosis is one of the phenotypic signatures of cancer(Hanahan D. et al., Cell 2000, 100, 57-70).

The anti-apoptotic proteins of the Bcl-2 family are associated withnumerous pathologies. The involvement of proteins of the Bcl-2 family isdescribed in numerous types of cancer, such as colorectal cancer, breastcancer, small-cell lung cancer, non-small-cell lung cancer, bladdercancer, ovarian cancer, prostate cancer, chronic lymphoid leukaemia,follicular lymphoma, myeloma, etc. Overexpression of the anti-apoptoticproteins of the Bcl-2 family is involved in tumorigenesis, in resistanceto chemotherapy and in the clinical prognosis of patients affected bycancer. There is, therefore, a therapeutic need for compounds thatinhibit the anti-apoptotic activity of the proteins of the Bcl-2 family.

In addition to being new, the compounds of the present invention havepro-apoptotic properties making it possible to use them in pathologiesinvolving a defect in apoptosis, such as, for example, in the treatmentof cancer, auto-immune diseases and diseases of the immune system.

The present invention relates more especially to compounds of formula(I):

wherein:

-   -   A₁ and A₂, each independently of the other, represent a hydrogen        or halogen atom, a linear or branched (C₁-C₆)polyhaloalkyl        group, a linear or branched (C₁-C₄)alkyl group or a cycloalkyl        group,    -   T represents a hydrogen atom, a linear or branched (C₁-C₆)alkyl        group optionally substituted by from one to three halogen atoms,        a group (C₁-C₄)alkyl-NR₁R₂, or a group (C₁-C₄)alkyl-OR₆,    -   R₁ and R₂, each independently of the other, represent a hydrogen        atom or a linear or branched (C₁-C₆)alkyl group, or R₁ and R₂        form with the nitrogen atom carrying them a heterocycloalkyl,    -   R₃ represents a linear or branched (C₁-C₆)alkyl group, a linear        or branched (C₂-C₆)alkenyl group, a linear or branched        (C₂-C₆)alkynyl group, a cycloalkyl group, a        (C₃-C₁₀)cycloalkyl-(C₁-C₆)alkyl group wherein the alkyl moiety        is linear or branched, a heterocycloalkyl group, an aryl group        or a heteroaryl group, it being understood that one or more of        the carbon atoms of the preceding groups, or of their possible        substituents, may be deuterated,    -   R₄ represents an aryl group, a heteroaryl group, a cycloalkyl        group or a linear or branched (C₁-C₆)alkyl group, it being        understood that one or more of the carbon atoms of the preceding        groups, or of their possible substituents, may be deuterated,    -   R₅ represents a hydrogen or halogen atom, a linear or branched        (C₁-C₆)alkyl group, or a linear or branched (C₁-C₆)alkoxy group,    -   R₆ represents a hydrogen atom or a linear or branched        (C₁-C₆)alkyl group,    -   R_(a), R_(b), R_(c) and R_(d), each independently of the others,        represent R₇, a halogen atom, a linear or branched (C₁-C₆)alkoxy        group, a hydroxy group, a linear or branched        (C₁-C₆)polyhaloalkyl group, a trifluoromethoxy group, —NR₇R₇′,        nitro, R₇—CO—(C₁-C₆)alkyl-, R₇—CO—NH—(C₀-C₆)alkyl-,        NR₇R₇′—CO—(C₀-C₆)alkyl-, NR₇R₇′—CO—(C₀-C₆)alkyl-O—,        R₇—SO₂—NH—(C₀-C₆)alkyl-, R₇—NH—CO—NH—(C₀-C₆)alkyl-,        R₇—O—CO—NH—(C₀-C₆)alkyl-, a heterocycloalkyl group, or the        substituents of one of the pairs (R_(a),R_(b)), (R_(b),R_(c)) or        (R_(c),R_(d)) form together with the carbon atoms carrying them        a ring composed of from 5 to 7 ring members, which may contain        from one to 2 hetero atoms selected from oxygen and sulphur, it        also being understood that one or more carbon atoms of the ring        defined hereinbefore may be deuterated or substituted by from        one to 3 groups selected from halogen and linear or branched        (C₁-C₆)alkyl,    -   R₇ and R₇′, each independently of the other, represent a        hydrogen, a linear or branched (C₁-C₆)alkyl, a linear or        branched (C₂-C₆)alkenyl, a linear or branched (C₂-C₆)alkynyl, an        aryl or a heteroaryl, or R₇ and R₇′, together with the nitrogen        atom carrying them, form a heterocycle composed of from 5 to 7        ring members,        it being understood that:    -   “aryl” means a phenyl, naphthyl, biphenyl or indenyl group,    -   “heteroaryl” means any mono- or bi-cyclic group composed of from        5 to 10 ring members, having at least one aromatic moiety and        containing from 1 to 4 hetero atoms selected from oxygen,        sulphur and nitrogen (including quaternary nitrogens),    -   “cycloalkyl” means any mono- or bi-cyclic, non-aromatic,        carbocyclic group containing from 3 to 10 ring members,    -   “heterocycloalkyl” means any mono- or bi-cyclic, non-aromatic,        condensed or spiro group composed of from 3 to 10 ring members        and containing from 1 to 3 hetero atoms selected from oxygen,        sulphur, SO, SO₂ and nitrogen,        it being possible for the aryl, heteroaryl, cycloalkyl and        heterocycloalkyl groups so defined and the groups alkyl,        alkenyl, alkynyl and alkoxy to be substituted by from 1 to 3        groups selected from optionally substituted, linear or branched        (C₁-C₆)alkyl, (C₃-C₆)spiro, optionally substituted, linear or        branched (C₁-C₆)alkoxy, (C₁-C₆)alkyl-S—, hydroxy, oxo (or        N-oxide where appropriate), nitro, cyano, —COOR′, —OCOR′, NR′R″,        linear or branched (C₁-C₆)polyhaloalkyl, trifluoromethoxy,        (C₁-C₆)alkylsulphonyl, halogen, optionally substituted aryl,        heteroaryl, aryloxy, arylthio, cycloalkyl, heterocycloalkyl        optionally substituted by one or more halogen atoms or alkyl        groups, it being understood that R′ and R″, each independently        of the other, represent a hydrogen atom or an optionally        substituted, linear or branched (C₁-C₆)alkyl group,        to their enantiomers and diastereoisomers, and to addition salts        thereof with a pharmaceutically acceptable acid or base.

Among the pharmaceutically acceptable acids there may be mentioned,without implying any limitation, hydrochloric acid, hydrobromic acid,sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid,lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid,fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid,oxalic acid, methanesulphonic acid, camphoric acid etc.

Among the pharmaceutically acceptable bases there may be mentioned,without implying any limitation, sodium hydroxide, potassium hydroxidc,tricthylaminc, tert-butylamine etc.

Advantageously, A₁ represents a hydrogen atom or a methyl group.

Furthermore, A₂ preferably represents a linear or branched (C₁-C₆)alkylgroup optionally substituted by a group selected from halogen, hydroxy,linear or branched (C₁-C₆)alkoxy, NR′R″ and morpholine.

In another embodiment of the invention, A₂ represents a linear orbranched (C₁-C₆)polyhaloalkyl group or a cyclopropyl group.

Even more preferably, A₁ and A₂ both represent a methyl group.

In a preferred embodiment of the invention, T represents a linear orbranched (C₁-C₆)alkyl. In another preferred embodiment, T represents agroup alkyl(C₁-C₄)—NR₁R₂, and more particularly a groupalkyl(C₁-C₄)—NR₁R₂ wherein R₁ and R₂ form with the nitrogen atomcarrying them a heterocycloalkyl.

In preferred compounds of the invention, T represents a methyl,aminomethyl, (morpholin-4-yl)methyl, (4-methylpiperazin-1-yl)methyl,2-(morpholin-4-yl)ethyl, [2-(morpholin-4-yl)ethoxy]methyl,hydroxymethyl, [2-(dimethylamino)ethoxy]methyl,hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl,1-oxa-6-azaspiro[3.3]hept-6-yl-methyl, 3-(morpholin-4-yl)propyl ortrifluoromethyl group. Even more preferably, T represents a(morpholin-4-yl)methyl, methyl or 3-(morpholin-4-yl)propyl group.

Preferably, R_(a) and R_(d) each represent a hydrogen atom and(R_(b),R_(c)), together with the carbon atoms carrying them, form a1,3-dioxolane group or a 1,4-dioxane group; or R_(a), R_(c) and R_(d)each represent a hydrogen atom and R_(b) represents a hydrogen orhalogen atom or a methoxy group. Even more preferably, R_(a) and R_(d)each represent a hydrogen atom and (R_(b),R_(c)), together with thecarbon atoms carrying them, form a 1,3-dioxolane group; or R_(a), R_(c)and R_(d) each represent a hydrogen atom and R_(b) represents a halogen,preferably a chlorine or fluorine atom.

In another embodiment of the invention, R_(a) and R_(d) each represent ahydrogen atom, R_(b) represents a hydrogen or halogen atom and R_(c) ahydroxy or methoxy group, or; R_(a) and R_(d) each represent a hydrogenatom, R_(b) represents a hydroxy or methoxy group and R_(c) a halogenatom.

Alternatively, R_(a), R_(b) and R_(d) advantageously each represent ahydrogen atom and R_(c) represents a group selected fromR₇—CO—NH—(C₀-C₆)alkyl-, R₇—SO₂—NH—(C₀-C₆)alkyl-,R₇—NH—CO—NH—(C₀-C₆)alkyl- and R₇—O—CO—NH—(C₀-C₆)alkyl-. For thosespecific compounds, R₃ preferably represents a linear or branched(C₁-C₆)alkyl or a heteroaryl optionally substituted by a linear orbranched (C₁-C₆)alkyl, and R₄ represents a 4-hydroxyphenyl group. Evenmore preferably, R₃ represents a methyl.

Preferred R₄ groups are as follows: phenyl; 4-hydroxyphenyl;3-fluoro-4-hydroxyphenyl; 2-hydroxypyrimidine; 3-hydroxypyridine. Evenmore preferably, 114 represents a 4-hydroxyphenyl group.

In preferred compounds of the invention, R₃ represents a linear orbranched (C₁-C₆)alkyl group (preferably methyl), aryl or heteroaryl, allbeing optionally substituted. The groups aryl and heteroaryl are moreespecially preferred. Finally, R₃ preferably represents a group selectedfrom phenyl, 1H-pyrazole, 1H-indole, 1H-indazole, pyridine, pyrimidine,1H-pyrrolo[2,3-b]pyridine, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine,1H-benzimidazole, 1H-pyrrole, 1H-pyrrolo[2,3-c]pyridine,1H-pyrrolo[3,2-b]pyridine, 5H-pyrrolo[3,2-d]pyrimidine, thiophene,pyrazine, 1H-pyrazolo[3,4-h]pyridine, 1,2-oxazole, and1H-pyrazolo[1,5-a]pyrimidine, those groups optionally having one or moresubstituents selected from halogen, linear or branched (C₁-C₆)alkyl,linear or branched (C₁-C₆)alkoxy, cyano, cyclopropyl, oxetane,tetrahydrofuran, —CO—O—CH₃, trideuteriomethyl, 2-(morpholin-4-yl)ethyland 2-(morpholin-4-yl)ethoxy. More preferably, R₃ represents a group1-methyl-1H-pyrazol-4-yl, pyridin-4-yl,1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl, 5-cyano-1-methyl-1H-pyrrol-3-yl,5-cyano-1,2-dimethyl-1H-pyrrol-3-yl,1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl,5-cyano-2-methyl-1-(trideuteriomethyl)-1H-pyrrol-3-yl.

Preferred compounds according to the invention are included in thefollowing group:

-   5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide,-   5-(5-chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(pyridin-4-yl)-1H-pyrrole-3-carboxamide,-   N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide,-   N-(4-hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(pyridin-4-yl)-1H-pyrrole-3-carboxamide,-   5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide,-   5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide,-   5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(pyridin-4-yl)-1H-pyrrole-3-carboxamide,-   5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1-methyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide,-   N-(5-cyano-1-methyl-1H-pyrrol-3-yl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-yl-methyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide,-   5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide,-   5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide,-   N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-yl-methyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide,-   5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-[5-cyano-2-methyl-1-(trideuteriomethyl)-1H-pyrrol-3-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide,    their enantiomers and diastereoisomers, and addition salts thereof    with a pharmaceutically acceptable acid or base.

The invention relates also to a process for the preparation of compoundsof formula (I), which process is characterised in that there is used asstarting material the compound of formula (II):

wherein R_(a), R_(b), R_(c) and R_(d) are as defined for formula (I),which compound of Formula (II) is subjected to a Heck reaction, in anaqueous or organic medium, in the presence of a palladium catalyst, of abase, of a phosphine and of the compound of formula (III):

wherein the groups A₁ and A₂ are as defined for formula (I) and Alkrepresents a linear or branched (C₁-C₆)alkyl,to obtain the compound of formula (IV):

wherein A₁, A₂, R_(a), R_(b), R_(c) and R_(d) are as defined for formula(1) and Alk is as defined hereinbefore,the aldehyde function of which compound of formula (IV) is oxidised to acarboxylic acid to form the compound of formula (V):

wherein A₁, A₂, R_(a), R_(b), R_(c) and R_(d) are as defined for formula(1) and Alk is as defined hereinbefore,which compound of formula (V) is then subjected to peptide coupling witha compound of formula (VI):

wherein T and R₅ are as defined for formula (I),to yield the compound of formula (VII):

wherein A₁, A₂, R_(a), R_(b), R_(c), R_(d), T and R₅ are as defined forformula (I) and Alk is as defined hereinbefore,the ester function of which compound of formula (VII) is hydrolysed toyield the to corresponding carboxylic acid or carboxylase, which may beconverted into an acid derivative such as the corresponding acylchloride or anhydride before being coupled with an amine NHR₃R₄ whereinR₃ and R₄ have the same meanings as for formula (I), to yield thecompound of formula (I),which compound of formula (I) may be purified according to aconventional separation technique, which is converted, if desired, intoits addition salts with a pharmaceutically acceptable acid or base andwhich is optionally separated into its isomers according to aconventional separation technique,it being understood that, at any time considered appropriate in thecourse of the above-described process, certain groups (hydroxy, amino .. . ) of the reagents or intermediates of synthesis may be protected andthen deprotected according to the requirements of synthesis.

More particularly, when one of the groups R₃ or R₄ of the amine NHR₃R₄is substituted by a hydroxy function, the latter may be subjectedbeforehand to a protection reaction prior to any coupling with thecarboxylic acid formed from the compound of formula (VII), or with acorresponding acid derivative thereof, the resulting protected compoundof formula (I) subsequently undergoes a deprotection reaction and isthen optionally converted into one to of its addition salts with apharmaceutically acceptable acid or base.

The present invention relates also to an alternative process for thepreparation of compounds of formula (I′), which are particular cases ofthe compounds of formula (I) as defined hereinbefore:

wherein:

-   -   A₁, A₂, R_(d), R_(d), R₃, R₄, T and R₅ are as defined for        formula (I),    -   R_(b) and R_(c) are such that one represents a hydrogen and the        other a group selected from R₇—CO—NH—(C₀-C₆)alkyl-,        R₇—SO₂—NH—(C₀-C₆)alkyl-, R₇—NH—CO—NH—(C₀-C₆)alkyl- and        R₇—O—CO—NH—(C₀-C₆)alkyl-,        which preparation process uses as starting material a compound        of formula (II′):

wherein:

-   -   R_(a) and R_(d) are as defined for formula (I),    -   Hal represents a halogen atom,    -   X₁ and X₂ are such that one represents a (C₀-C₆)alkyl-NH₂ group        while the other represents a hydrogen atom,        which compound of formula (II′) is then subjected to peptide        coupling with a compound of formula (VI):

wherein T and R₅ are as defined for formula (I),to yield the compound of formula (III′):

wherein:

-   -   R_(a), R_(d), T and R₅ are as defined for formula (I),    -   Hal represents a halogen atom,    -   X₁ and X₂ are such that one represents a (C₀-C₆)alkyl-NH₂ group        while the other represents a hydrogen atom,        which compound of formula (III′) is subjected to a Heck        reaction, in an aqueous or organic medium, in the presence of a        palladium catalyst, of a base, of a phosphine and of a compound        of formula (IV′):

wherein A₁, A₂, R₃ and R₄ are as defined for formula (I),to form the compound of formula (V′):

wherein:

-   -   A₁, A₂, R_(a), R_(d), R₃, R₄, T and R₅ are as defined for        formula (1),    -   X₁ and X₂ are such that one represents a (C₀-C₆)alkyl-NH₂ group        while the other represents a hydrogen atom,        which compound of formula (V′) is then subjected to an acylation        or sulphonylation reaction to yield the compound of formula        (I′),        which compound of formula (I′) may be purified according to a        conventional separation technique, which is converted, if        desired, into its addition salts with a pharmaceutically        acceptable acid or base and which is optionally separated into        its isomers according to a conventional separation technique,        it being understood that, at any time considered appropriate in        the course of the above-described process, certain groups        (hydroxy, amino . . . ) of the reagents or intermediates of        synthesis may be protected and then deprotected according to the        requirements of synthesis.

The compounds of formulae (II), (III), (II′), (IV′), (VI) and the amineNHR₃R₄ are either commercially available or can be obtained by theperson skilled in the art using conventional chemical reactionsdescribed in the literature.

Pharmacological study of the compounds of the invention has shown thatthey have pro-apoptotic properties. The ability to reactivate theapoptotic process in cancerous cells is of major therapeutic interest inthe treatment of cancers, auto-immune diseases and diseases of theimmune system.

More especially, the compounds according to the invention will be usefulin the treatment of chemo- or radio-resistant cancers, and in malignanthaemopathies and small-cell lung cancer.

Among the cancer treatments envisaged there may be mentioned, withoutimplying any limitation, cancers of the bladder, brain, breast anduterus, chronic lymphoid leukaemias, colorectal cancer, cancers of theoesophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas,melanomas, malignant haemopathies, myelomas, ovarian cancer,non-small-cell lung cancer, prostate cancer and small-cell lung cancer.Among non-Hodgkin lymphomas, there may be mentioned more preferablyfollicular lymphomas, mantle cell lymphomas, diffuse large B-celllymphomas, small lymphocytic lymphomas and marginal zone B-celllymphomas.

The present invention relates also to pharmaceutical compositionscomprising at least one compound of formula (I) in combination with oneor more pharmaceutically acceptable excipients.

Among the pharmaceutical compositions according to the invention theremay be to mentioned more especially those that are suitable for oral,parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocularor respiratory administration, especially tablets or drages, sublingualtablets, sachets, paquets, capsules, glossettes, lozenges,suppositories, creams, ointments, dermal gels, and drinkable orinjectable ampoules.

The dosage varies according to the sex, age and weight of the patient,the administration route, the nature of the therapeutic indication, orof any associated treatments, and ranges from 0.01 mg to 1 g per 24hours in one or more administrations.

Furthermore, the present invention relates also to the association of acompound of formula (I) with an anticancer agent selected from genotoxicagents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinaseinhibitors and antibodies, and also to pharmaceutical compositionscomprising that type of association and their use in the manufacture ofmedicaments for use in the treatment of cancer.

The compounds of the invention may also be used in association withradiotherapy in the treatment of cancer.

Finally, the compounds of the invention may be linked to monoclonalantibodies or fragments thereof or linked to scaffold proteins that canbe related or not to monoclonal antibodies.

Antibody fragments must be understood as fragments of Fv, scFv, Fab,F(ab′)2, F(ab′), scFv-Fc type or diabodies, which generally have thesame specificity of binding as the antibody from which they aredescended. According to the present invention, antibody fragments of theinvention can be obtained starting from antibodies by methods such asdigestion by enzymes, such as pepsin or papain, and/or by cleavage ofthe disulfide bridges by chemical reduction. In another manner, theantibody fragments comprised in the present invention can be obtained bytechniques of genetic recombination likewise well known to the personskilled in the art or else by peptide synthesis by means of, forexample, automatic peptide synthesizers such as those supplied by thecompany Applied Biosystems, etc.

Scaffold proteins that can be related or not to monoclonal antibodiesare understood to mean a protein that contains or not an immunoglobulinfold and that yields a binding capacity similar to a monoclonalantibody. The man skilled in the art knows how to select the proteinscaffold. More particularly, it is known that, to be selected, such ascaffold should display several features as follow (Skerra A., J. Mol.Recogn., 13, 2000, 167-187): phylogenetically good conservation, robustarchitecture with a well-known three-dimensional molecular organization(such as, for example, crystallography or NMR), small size, no or only alow degree of post-translational modifications, easy to produce, expressand purify. Such a protein scaffold can be, but without limitation, astructure selected from the group consisting in fibronectin andpreferentially the tenth fibronectin type III domain (FNfn10),lipocalin, anticalin (Skerra A., J. Biotechnol., 2001, 74(4):257-75),the protein Z derivative from the domain B of staphylococcal protein A,thioredoxin A or any protein with a repeated domain such as an “ankyrinrepeat” (Kohl et al., PNAS, 2003, vol. 100, No. 4, 1700-1705),“armadillo repeat”, “leucine-rich repeat” or “tetratricopeptide repeat”.There could also be mentioned a scaffold derivative from toxins (suchas, for example, scorpion, insect, plant or mollusc toxins) or proteininhibitors of neuronal nitric oxide synthase (PIN).

The following Preparations and Examples illustrate the invention withoutlimiting it in any way.

Preparation 1:4-Chloro-2-[4-(ethoxycarbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]benzoic AcidStep A: Ethyl 1,2-dimethyl-1H-pyrrole-3-carboxylate

To a solution of 10 g of ethyl 2-methyl-1H-pyrrole-3-carboxylate (65.3mmol) and 8.95 mL (130.6 mmol) of methyl iodide in 70 mL ofdimethylformamide placed at 0° C. there are added, in three portions,2.61 g (65.3 mmol) of sodium hydride (NaH) 60%. The batch is thenstirred at 0° C. for 1 hour. Then, the reaction mixture is hydrolysed bythe addition of 420 mL of ice-cold water. The reaction mixture is thendiluted with ethyl acetate, successively washed with 0.1M aqueoushydrochloric acid (HCl) solution, saturated aqueous LiCl solution andthen brine. The organic phase is then dried over MgSO₄, filtered,concentrated to dryness and purified by chromatography over silica gel(petroleum ether/AcOEt gradient).

¹H NMR: δ (400 MHz; dmso-d₆; 300K): 6.65 (d, 1H pyrrole); 6.3 (1d, 1Hpyrrole); 4.1 (1q, 2H, OCH₂CH₃); 3.5 (s, 3H N-pyrrole); 2.4 (s, 3Hpyrrole); 1.5 (It, 3H OCH₂CH₃)

IR: ν: >C═O: 1688 cm⁻¹; ν: C—O—C: 1172 cm⁻¹

Step B: Ethyl5-(5-chloro-2-formylphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylate

To a solution of 10.5 g of the compound obtained in Step A (62.8 mmol)in 65 mL of N,N-dimethylacetamide there are successively added 15.2 g of2-bromo-4-chlorobenzaldehyde (69 mmol), 12.3 g of potassium acetate(125.6 mmol) and then the batch is stirred under argon for 20 minutes.There are then added 2.2 g of palladium catalyst PdCl₂(PPh₃)₂ (3.14mmol). The reaction mixture is then heated at 130° C. overnight. Themixture is allowed to return to ambient temperature and it is thendiluted with dichloromethane. Animal charcoal is added (2 g per g ofproduct) and the batch is stirred at ambient temperature for 1 hour andthen filtered. The organic phase is then washed with water, dried overMgSO₄ and concentrated to dryness. The crude product thereby obtained ispurified by chromatography over silica gel (petroleum ether/AcOEtgradient). The title product is obtained in the form of a solid.

¹H NMR: δ (400 MHz; dmso-d6; 300K): 9.8 (s, 1H, formyl); 7.91-7.69-7.61(d, 3H, aromatic Hs); 6.5 (s, 1H pyrrole); 4.2 (q, 2H, OCH₂CH₃); 3.4 (s,3H, CH₃—N-pyrrole); 2.55 (s, 3H pyrrole); 1.28 (t, 3H, OCH₂CH₃)

Step C:4-Chloro-2-[4-(ethoxycarbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]benzoic Acid

A solution is prepared containing 12.85 g of the compound obtained inStep B (42 mmol) and 35.7 mL (336 mmol) of 2-methyl-2-butene in amixture containing 20 mL of acetone and 20 mL of tetrahydrofuran. Thereare added, dropwise, 200 mL of an aqueous solution containing a mixtureof 13.3 g of sodium chlorite (NaClO₂) (147 mmol) and 14.5 g of sodiumhydrogen phosphate (NaHPO₄) (105 mmol). The batch is then vigorouslystirred at ambient temperature for 7 hours. The reaction mixture is thenconcentrated to remove the acetone. Ethyl acetate is added, and theorganic phase is washed with water, dried over MgSO₄ and thenconcentrated to dryness. The residue is then taken up in a minimum ofethyl ether. The solid then obtained is filtered off, washed with etherand then dried in vacuo at 40° C. overnight. The title product isobtained in the form of a solid, which is subsequently used withoutbeing otherwise purified.

¹H NMR: δ (400 MHz; dmso-d6; 300K): 13 (m, 1H COOH); 7.85-7.6-7.41 (d,dd, wd, 3H, aromatic Hs); 6.3 (s, 1H, H pyrrole); 4.15 (q, 2H, OCH₂CH₃);3.25 (s, 3H, CH₃—N-pyrrole); 2.5 (s, 3H, CH₃-pyrrole); 1.25 (t, 3H,OCH₂CH₃)

IR: ν: —OH: 3100-2500 cm⁻¹ acid; ν: >C═O: 1681 cm⁻¹ ester+acid

Preparation 2: 2-[4-(Ethoxycarbonyl)-1-methyl-1H-pyrrol-2-yl]benzoicAcid

The procedure is in accordance with the process of Preparation 1,replacing, on the one hand, the ethyl 2-methyl-1H-pyrrole-3-carboxylateused in Step A by ethyl 1H-pyrrole-3-carboxylate and, on the other hand,the 2-bromo-4-chlorobenzaldehyde used in Step B by 2-bromo-benzaldehyde.

Preparation 3:4-Chloro-2-[4-(ethoxycarbonyl)-1-methyl-1H-pyrrol-2-yl]benzoic Acid

The procedure is in accordance with the process of Preparation 1,replacing the ethyl 2-methyl-1H-pyrrole-3-carboxylate used in Step A byethyl 1H-pyrrole-3-carboxylate.

Preparation 4:6-[4-(Ethoxycarbonyl)-1-methyl-1H-pyrrol-2-yl]-1,3-benzodioxole-5-carboxylicAcid

The procedure is in accordance with the process of Preparation 1,replacing, on the one hand, the ethyl 2-methyl-1H-pyrrole-3-carboxylateused in Step A by ethyl 1H-pyrrole-3-carboxylate and, on the other hand,the 2-bromo-4-chlorobenzaldehyde used in Step B by6-bromo-1,3-benzodioxole-5-carbaldehyde.

IR: ν: —OH: 3500-2300 cm⁻¹ acid; ν: >C═O: 1688-1670 cm⁻¹ ester+acid

Preparation 5:4-Chloro-2-[4-(ethoxycarbonyl)-1-ethyl-1H-pyrrol-2-yl]benzoic Acid

The procedure is in accordance with the process of Preparation 1,replacing in Step A, on the one hand, the ethyl2-methyl-1H-pyrrole-3-carboxylate by ethyl 1H-pyrrole-3-carboxylate and,on the other hand, the methyl iodide by ethyl iodide (see the protocoldescribed in U.S. Pat. No. 6,258,805 B1).

Preparation 6:4-Chloro-2-[1-cyclopropyl-4-(ethoxycarbonyl)-1H-pyrrol-2-yl]benzoic Acid

The procedure is in accordance with the process of Preparation 1,replacing in Step A, on the one hand, the ethyl2-methyl-1H-pyrrole-3-carboxylate by ethyl 1H-pyrrole-3-carboxylate and,on the other hand, the methyl iodide by cyclopropylboronic acid (see theprotocol described in Bénard S. et al, Journal of Organic Chemistry73(16), 6441-6444, 2008).

Preparation 7:4-Chloro-2-[4-(ethoxycarbonyl)-1-(propan-2-yl)-1H-pyrrol-2-yl]-benzoicAcid

The procedure is in accordance with the process of Preparation 1,replacing in Step A, on the one hand, the ethyl2-methyl-1H-pyrrole-3-carboxylate by ethyl 1H-pyrrole-3-carboxylate and,on the other hand, the methyl iodide by isopropyl iodide (see theprotocol described in Okada E. et al, Heterocycles 34(7), 1435-1441,1992).

Preparation 8:4-Fluoro-2-[4-(methoxycarbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]benzoic Acid

The procedure is in accordance with the process of Preparation 1,replacing, in Step A, the ethyl 2-methyl-1H-pyrrole-3-carboxylate bymethyl 2-methyl-1H-pyrrole-3-carboxylate and also the2-bromo-4-chlorobenzaldehyde used in Step B by2-bromo-4-fluorobenzaldehyde.

IR: ν: —OH: 2727-2379 cm⁻¹ acid; ν: >C═O: 1687 cm⁻¹

Preparation 9:6-{1-[2-(Benzyloxy)ethyl]-4-(ethoxycarbonyl)-5-methyl-1H-pyrrol-2-yl}-1,3-benzodioxole-5-carboxylicAcid Step A: Ethyl1-[2-(benzyloxy)ethyl]-2-methyl-1H-pyrrole-3-carboxylase

The procedure is in accordance with the process of Step A of Preparation1, replacing the methyl iodide used as alkylating agent by benzyl2-bromoethyl ether.

¹H NMR: δ (400 MHz; dmso-d6; 300K): 7.32 (t, 2H, aromatic Hs, H metabenzyl ether); 7.3 (t, 1H, aromatic H, H para benzyl ether); 7.23 (d,2H, aromatic Hs, H ortho benzyl ether); 6.72 (d, 1H, H-pyrrole); 6.35(d, 1H, H-pyrrole); 4.48 (s, 2H, aliphatic Hs, O—CH₂-Ph); 4.15 (q, 2H,aliphatic Hs, O—CH₂—CH₃); 4.1 (t, 2H, aliphatic Hs, CH₂O—CH₂-Ph); 3.7(t, 2H, aliphatic Hs, CH₂—CH₂—O—CH₂-Ph); 2.45 (s, 3H, CH₃-pyrrole); 1.25(t, 3H, aliphatic Hs, O—CH₂—CH₃)

IR: ν: >C═O: 1689 cm⁻¹

Step B:6-{1-[2-(Benzyloxy)ethyl]-4-(ethoxycarbonyl)-5-methyl-1H-pyrrol-2-yl}-1,3-benzodioxole-5-carboxylicAcid

The procedure is in accordance with the processes of Steps B and C ofPreparation 1, replacing the 2-bromo-4-chlorobenzaldehyde by6-bromo-1,3-benzodioxole-5-carbaldehyde.

¹H NMR: δ (400 MHz; dmso-d6; 300K): 7.35 (s, 1H, aromatic H, Hbenzodioxole); 7.30 (m, 3H, aromatic Hs, H benzyl ether); 7.25 (s, 1H,aromatic H, 1-1 benzodioxole); 7.10 (d, 2H, aromatic Hs, H ortho benzylether); 12.55 (broad s, 1H, COOH); 6.75 (s, 1H, H-pyrrole); 6.15 (broads, 2H, aliphatic Hs, O—CH₂—O); 4.30 (s, 2H, aliphatic Hs, O—CH₂-Ph);4.15 (q, 2H, aliphatic Hs, O—CH₂—CH₃); 3.9 (m, 2H, aliphatic Hs,CH₂—CH₂O—CH₂-Ph); 3.40 (t, 2H, aliphatic Hs, CH₂—CH₂—O—CH₂-Ph); 2.50 (s,3H, CH₃-pyrrole); 1.25 (t, 3H, aliphatic Hs, O—CH₂—CH₃)

IR: ν: —OH: 3200-2300 cm⁻¹ acid; ν: >C═O: 1687 cm⁻¹ acid

Preparation 10:2-{1-[3-(Benzyloxy)propyl]-4-(ethoxycarbonyl)-5-methyl-1H-pyrrol-2-yl}-4-fluorobenzoicAcid

The procedure is in accordance with the process of Preparation 9,replacing the benzyl 2-bromoethyl ether used in Step A by benzyl3-bromopropyl ether and also the 6-bromo-1,3-benzodioxole-5-carbaldehydeused in Step B by 2-bromo-4-fluorobenzaldehyde.

IR: ν: —OH: 3200-2305 cm⁻¹ acid; ν: >C═O: 1690 cm⁻¹ acid

Preparation 11:6-[4-(Ethoxycarbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-1,3-benzo-dioxole-S-carboxylicAcid

The procedure is in accordance with the process of Preparation 1,replacing the 2-bromo-4-chlorobenzaldehyde used in Step B by6-bromo-1,3-benzodioxole-5-carbaldehyde.

Preparation 12:4-Methoxy-2-[4-(methoxycarbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-benzoicAcid

The procedure is in accordance with the process of Preparation 1,replacing the ethyl 2-methyl-1H-pyrrole-3-carboxylate used in Step A bymethyl 2-methyl-1H-pyrrole-3-carboxylate and also the2-bromo-4-chlorobenzaldehyde used in Step B by2-bromo-4-methoxybenzaldehyde.

IR: ν: —OH: 3000-2500 cm⁻¹ acid; ν: >C═O: 1693+1670 cm⁻¹ acid+ester

Preparation 13:7-[4-(Methoxycarbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-2,3-dihydro-1,4-benzodioxin-6-carboxylicAcid

The procedure is in accordance with the process of Preparation 1,replacing in Step A the ethyl 2-methyl-1H-pyrrole-3-carboxylate bymethyl 2-methyl-1H-pyrrole-3-carboxylate and also the2-bromo-4-chlorobenzaldehyde used in Step B by7-bromo-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde.

IR: ν: —OH: 3100-2500 cm⁻¹ acid; ν: >C═O: 1690+1674 cm⁻¹ acid+ester

Preparation 14:4-Fluoro-5-methoxy-2-[4-(methoxycarbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]benzoicAcid

The procedure is in accordance with the process of Preparation 1,replacing in Step A the ethyl 2-methyl-1H-pyrrole-3-carboxylate bymethyl 2-methyl-1H-pyrrole-3-carboxylate and also the2-bromo-4-chlorobenzaldehyde used in Step B by2-bromo-4-fluoro-5-methoxybenzaldehyde.

Preparation 15:4-Fluoro-5-hydroxy-2-[4-(methoxycarbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]benzoicAcid

The procedure is in accordance with the process of Preparation 1,replacing in Step A the ethyl 2-methyl-1H-pyrrole-3-carboxylate bymethyl 2-methyl-1H-pyrrole-3-carboxylate and also the2-bromo-4-chlorobenzaldehyde used in Step B by2-bromo-4-fluoro-5-hydroxy-benzaldehyde.

Preparation 16:6-[4-(Ethoxycarbonyl)-1-methyl-5-trifluoromethyl-1H-pyrrol-2-yl]-1,3-benzodioxole-5-carboxylicAcid

The procedure is in accordance with the process of Preparation 1,replacing in Step A the ethyl 2-methyl-1H-pyrrole-3-carboxylate by ethyl2-(trifluoromethyl)-1H-pyrrole-3-carboxylate and also the2-bromo-4-chlorobenzaldehyde used in Step B by6-bromo-1,3-benzodioxole-5-carbaldehyde.

Preparation 17:6-[4-(Ethoxycarbonyl)-1-ethyl-5-methyl-1H-pyrrol-2-yl]-1,3-benzodioxole-5-carboxylicAcid

The procedure is in accordance with the process of Preparation 11,replacing the methyl iodide by ethyl iodide (see the protocol describedin U.S. Pat. No. 6,258,805 B1).

Preparation 18:6-[4-(Ethoxycarbonyl)-1-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-1,3-benzodioxole-5-carboxylicAcid Step A: Ethyl 1-methyl-2-(trifluoromethyl)pyrrole-3-carboxylate

Ethyl 4,4,4-trifluoro-3-oxo-butanoate (29 ml, 0.219 mmol) is added tomethylamine (40% solution in water) (50 ml, 0.580 mmol) cooled to 10°C.; a white precipitate forms. 1,2-Dibromoethyl acetate (preparedaccording to Molecules, 16, 9368-9385; 2011) is added dropwise. Thereactor is then sealed and heated at 70° C. for 45 minutes. The reactionmixture is cooled, then extracted with ethyl acetate, dried over sodiumsulphate (Na₂SO₄) and evaporated to dryness. The crude reaction productobtained is purified by chromatography over silica gel using heptane andethyl acetate as eluants. The expected compound is obtained in the formof crystals.

¹H NMR (400 MHz, dmso-d6) δ ppm: 7.11 (d, 1H), 6.52 (d, 1H), 4.21 (quad,2H), 3.8 (s, 3H), 1.27 (t, 3H)

¹⁹F NMR (400 MHz, dmso-d6) δ ppm: −53.9

IR (ATR) mil 3145+3128 ν —CH, 1711 ν>C═O, 1183+1117+1078 ν —CF3

Step B:6-[4-(Ethoxycarbonyl)-1-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-1,3-benzo-dioxole-5-carboxylicAcid

The procedure is in accordance with the protocol described in Steps Band C of Preparation 1, replacing the 2-bromo-4-chlorobenzaldehyde usedin Step B by 6-bromo-1,3-benzodioxole-5-carbaldehyde.

Preparation 19:6-[1-(2-Benzyloxyethyl)-4-ethoxycarbonyl-5-methyl-1H-pyrrol-2-yl]-1,3-benzodioxole-5-carboxylicAcid Step A; Ethyl 1-(2-benzyloxyethyl)-2-methyl-pyrrole-3-carboxylate

Ethyl 2-methyl-1H-pyrrole-3-carboxylate (10 g, 65.3 mmol) is dissolvedin 100 mL of dimethylformamide under argon cooled to 0° C., and then2-bromoethoxymethylbenzene (28.1 g, 130.6 mmol) is added all at once.The reaction mixture is placed under stirring. There is then addedthereto, at 0° C., in three portions, NaH (1.72 g, 71.83 mmol) over aperiod of 15 minutes. The reaction mixture is stirred for 15 minutes at0° C., and then for 15 hours at ambient temperature. It is then pouredinto an ice bath and then extracted 3 times with ethyl acetate. Theorganic phase is washed 3 times with saturated aqueous lithium chloridesolution, dried over MgSO₄, filtered and then evaporated to dryness. Theresidue thereby obtained is purified by chromatography over silica gelusing petroleum ether and ethyl acetate as eluants. The expectedcompound is obtained in the form of an oil.

¹H NMR (400 MHz, dmso-d6) δ ppm: 7.32 (t, 2H), 7.3 (t, 1H), 7.23 (d,2H), 6.72 (d, 1H), 6.35 (d, 1H), 4.48 (s, 2H), 4.15 (quad., 2H), 4.1 (t,2H), 3.7 (t, 2H), 2.45 (s, 3H), 1.25 (t, 3H)

IR (ATR) cm⁻¹: 1689 ν —C═O

Step B: Ethyl1-(2-benzyloxyethyl)-5-(6-formyl-1,3-benzodioxol-5-yl)-2-methyl-pyrrole-3-carboxylate

The procedure is in accordance with the process of Step B of Preparation1, replacing the 2-bromo-4-chlorobenzaldehyde by6-bromo-1,3-benzodioxole-5-carbaldehyde.

¹H NMR (400 MHz, dmso-d6) δ ppm: 9.5 (s, 1H), 7.3 (s, 1H), 7.25 (m, 3H),7.05 (m, 2H), 7 (s, 1H), 6.4 (s, 1H), 6.2 (bs, 2H), 4.25 (s, 2H), 4.2(quad., 2H), 4.05 (m, 2H), 3.4 (m, 2H), 2.55 (s, 3H), 1.25 (t, 3H)

Step C:6-[1-(2-Benzyloxyethyl)-4-ethoxycarbonyl-5-methyl-1H-pyrrol-2-yl]-1,3-benzo-dioxole-5-carboxylicAcid

The procedure is in accordance with the process of Step C of Preparation1.

¹H NMR (400 MHz, dmso-d6) δ ppm: 12.55 (bs, 1H), 7.35 (s, 1H), 7.3 (m,3H), 7.2 (m, 3H), 6.75 (s, 1H), 6.15 (s, 2H), 4.3 (s, 2H), 4.15 (quad.,2H), 3.9 (m, 2H), 3.4 (t, 2H), 2.5 (s, 3H), 1.25 (t, 3H)

IR (ATR) cm⁻¹: 3200-2300 ν —OH, 1687 (+ shoulder) ν —C═O carboxylicacid+conjugated ester

Preparation 20:6-[4-(Ethoxycarbonyl)-1-ethyl-5-methyl-1H-pyrrol-2-yl]-1,3-benzo-dioxole-5-carboxylicAcid

The procedure is in accordance with the protocol described inPreparation 11, replacing the methyl iodide by ethyl iodide.

¹H NMR (400 MHz, dmso-d6) δ ppm: 12.49 (bs, 1H), 7.33 (s, 1H), 6.89 (s,1H), 6.17 (s, 2H), 6.13 (s, 1H), 4.15 (quad, 2H), 3.69 (quad, 2H), 2.51(s, 3H), 1.24 (t, 3H), 1.01 (t, 3H)

Preparation 21:6-[4-(Ethoxycarbonyl)-1-(2-fluoroethyl)-5-methyl-1H-pyrrol-2-yl]-1,3-benzodioxole-5-carboxylicAcid

The procedure is in accordance with the process of Preparation 11,replacing the methyl iodide by 1-bromo-2-fluoroethane.

¹H NMR (400 MHz, dmso-d6, 300K) δ ppm: 12.53 (bs, 1H), 7.34 (s, 1H), 6.9(s, 1H), 6.16 (s, 1H), 6.16 (s, 2H), 4.4 (dt, 2H), 4.15 (quad, 2H), 4.01(m, 2H), 2.51 (s, 3H), 1.24 (t, 3H)

¹⁹F NMR (400 MHz, dmso-d6, 300 K) δ ppm: −222

IR: ν: —OH: 3700-2400 cm⁻¹ acid; ν: >C═O: 1689 cm⁻¹ acid; ν: >CF: 1213cm⁻¹

Preparation 22:6-{4-(Ethoxycarbonyl)-1-methyl-5-[2-(morpholin-4-yl)ethyl]-1H-pyrrol-2-yl}-1,3-benzodioxole-5-carboxylicAcid Step A: 3,3-Diethoxypropanoic Acid

To a solution of 25 g of ethyl 3,3-diethoxypropionate (131 mmol) in 79mL of methanol there are added 13.1 mL of aqueous 35% sodium hydroxidesolution (452 mmol). The reaction mixture is stirred at ambienttemperature for 3 hours. The reaction mixture is then concentrated toremove the methanol. After dissolving the undissolved material by addingwater, aqueous 5N HCl solution is added to obtain a pH of 5.Dichloromethane is added and then the organic phase is washed withbrine. After drying over MgSO₄ and concentrating to dryness, the titleproduct is obtained in the form of an oil which is used in the next Stepwithout being otherwise purified.

¹H NMR (400 MHz, dmso-d6) δ ppm: 12.2 (s, 1H), 4.8 (t, 1H), 3.58/3.47(2m, 4H), 2.5 (d, 2H), 1.09 (t, 6H)

Step B: Ethyl 5,5-diethoxy-3-oxo-pentanoate

To a solution of 16 mL of 3-ethoxy-3-oxomalonic acid (135 mmol) in 40 mLof tetrahydrofuran there are added, under argon, 21.9 g of powderedmagnesium (90.4 mmol). The mixture obtained is then heated at 80° C. for7 hours. After returning to ambient temperature, this mixture istransferred by cannula to a solution of 10 g of the compound obtained inStep A (61.7 mmol) in 64 mL of tetrahydrofuran to which there haspreviously been added, in portions, 11 g of carbonyldiimidazole (66mmol). The reaction mixture is stirred for 3 days at ambienttemperature. After concentration, the residue is taken up in a mixtureof ethyl acetate and aqueous sodium hydrogen sulphate (NaHSO₄) solution.The mixture is stirred vigorously until no more gas is evolved. Afterseparation of the phases, the organic phase is washed successively withwater, saturated aqueous NaHCO₃ solution and finally brine. After dryingover MgSO₄ and concentrating to dryness, the title product is obtainedin the form of an oil which is used in the next Step without beingotherwise purified.

¹H NMR (400 MHz, dmso-d6) δ ppm: 4.84 (t, 1H), 4.08 (q, 2H), 3.59 (s,2H), 3.56/3.46 (2m, 4H), 2.8 (d, 2H), 1.18 (t, 3H), 1.09 (t, 6H)

Step C: Ethyl 2-(2,2-diethoxyethyl)-1-methyl-pyrrole-3-carboxylate

To a solution of 11.8 g of the compound obtained in Step B (50.8 mmol)in 76 mL of water there are added, dropwise at 0° C., 6.6 ml of aqueous40% methylamine solution (76.2 mmol). The reaction mixture is stirredand gently reheated to ambient temperature over 5 hours. After returningto 0° C., 8.8 mL of aqueous 40% methylamine solution (102 mmol) and then16.6 mL of aqueous 50% chloroacetaldehyde solution (127 mmol) are eachadded dropwise at a temperature of less than 10° C. The reaction mixtureis stirred at ambient temperature for 16 hours and then diluted withethyl acetate. The organic phase is washed with brine, dried over MgSO₄and concentrated to dryness. The crude product thereby obtained ispurified by chromatography over silica gel using petroleum ether andethyl acetate as eluants. The title product is obtained in the form ofan oil.

¹H NMR (400 MHz, dmso-d6) δ ppm: 6.7 (d, 1H), 6.33 (d, 1H), 4.55 (t,1H), 4.15 (q, 2H), 3.6 (m, 2H), 3.6 (s, 3H), 3.3 (m, 2H), 3.15 (d, 2H),1.25 (1, 3H), 1.05 (t, 6H)

Step D: Ethyl 1-methyl-2-(2-morpholinoethyl)pyrrole-3-carboxylate

To a solution of 3.8 g of the compound obtained in Step C (14.05 mmol)in 28 mL of tetrahydrofuran there are added 58 mL of aqueous 10%sulphuric acid solution. The reaction mixture is stirred at ambienttemperature for 2 hours and then diluted with a mixture of ethyl acetateand water. After separation, the organic phase is washed with brine,dried over MgSO₄ and concentrated to dryness. To a solution of theresidue thereby obtained in 70 mL of dichloroethane there are added asolution of 13.5 mL of morpholine (14.5 mmol) in a mixture composed of30 mL of dichloroethane and 3.6 mL of 4N aqueous HCL solution in dioxane(14.5 mmol), and then 7.4 g of sodium triacetoxyborohydride (NaBH(OAc)₃)(35.13 mmol). The reaction mixture is stirred at ambient temperature for3 hours and then diluted with a mixture of dichloromethane and saturatedaqueous NaHCO₃ solution. After separation of the phases and extractionof the aqueous phase with dichloromethane, the organic phases are driedover MgSO₄ and concentrated to dryness. The crude product therebyobtained is purified by chromatography over silica gel usingdichloromethane and methanol as eluants. The title product is isolatedin the form of an oil.

¹H NMR (400 MHz, dmso-d6) δ ppm: 6.66 (d, 1H), 6.31 (d, 1H), 4.14 (q,2H), 3.58 (s, 3H), 3.57 (m, 4H), 3.05 (m, 2H), 2.45-2.38 (m, 6H), 1.24(t, 3H)

Step E:6-{4-(Ethoxycarbonyl)-1-methyl-5-[2-(morpholin-4-yl)ethyl]-1H-pyrrol-2-yl}-1,3-benzodioxole-5-carboxylicAcid

The procedure is in accordance with Steps B and C of Preparation, 1replacing the 2-bromo-4-chlorobenzaldehyde used in Step B by6-bromo-1,3-benzodioxole-5-carbaldehyde.

Preparation 23:6-[4-(Ethoxycarbonyl)-1-methyl-5-(morpholin-4-ylmethyl)-1H-pyrrol-2-yl]-1,3-benzodioxole-5-carboxylicAcid Step A: Ethyl 4,4-diethoxy-3-oxo-butanoate

To a solution of 40 g of ethyl diethoxyacetate (227 mmol) in 67 mL ofethyl acetate there are added under argon, in portions, 6 g of sodium(261 mmol). The reaction mixture is then stirred at ambient temperaturefor 48 hours. There are added 10 mL of methanol, and then the mixture ishydrolysed with 65 mL of water. The pH of the reaction mixture isadjusted to pH 6 by adding 1N aqueous HCl solution. The mixture isseparated and then extracted with ethyl acetate. The organic phases arecombined, washed with brine, dried over MgSO₄, filtered and concentratedto dryness. The title product is obtained in the form of an oil which isused in the next Step without being otherwise purified.

¹H NMR (400 MHz, CDCl₃) δ ppm: 3.6 (s, 2H), 1.28 (t, 9H), 3.7-3.6 (2m,4H), 4.7 (s, 1H), 4.2 (quad, 2H)

Step B: Ethyl 2-(2,2-diethoxymethyl)-1-methyl-pyrrole-3-carboxylate

The title compound is obtained in accordance with the process describedin Step C of Preparation 22, starting from the ethyl4,4-diethoxy-3-oxo-butanoate obtained in the preceding Step.

¹H NMR (400 MHz, dmso-d6) δ ppm: 6.73 (d, 1H), 6.32 (d, 1H), 6.23 (s,1H), 4.17 (q, 2H), 3.7 (s, 3H), 3.68/3.43 (2m, 4H), 1.26 (t, 3H), 1.13(t, 6H)

Step C: Ethyl 1-methyl-2-(2-morpholinomethyl)pyrrole-3-carboxylate

The title compound is obtained in accordance with the process describedin Step D of Preparation 22, starting from the ethyl2-(2,2-diethoxymethyl)-1-methyl-pyrrole-3-carboxylate obtained in thepreceding Step.

¹H NMR (400 MHz, dmso-d6) δ ppm: 6.74 (d, 1H), 6.32 (d, 1H), 4.15 (q,2H), 3.8 (s, 2H), 3.65 (s, 3H), 3.5 (m, 4H), 2.32 (m, 4H), 1.22 (t, 3H)

Step D:6-[4-(Ethoxycarbonyl)-1-methyl-5-(morpholin-4-ylmethyl)-1H-pyrrol-2-yl]-1,3-benzodioxole-5-carboxylicAcid

The procedure is in accordance with the protocol described in Steps Band C of Preparation 1, replacing the 2-bromo-4-chlorobenzaldehyde usedin Step B by 6-bromo-1,3-benzodioxole-5-carbaldehyde.

Preparation 24:6-[4-(Methoxycarbonyl)-5-(2-methoxyethyl)-1-methyl-1H-pyrrol-2-yl]-1,3-benzodioxole-5-carboxylicAcid Step A: Methyl 2-(2-methoxyethyl)-1-methyl-pyrrole-3-carboxylate

The title compound is obtained in accordance with the protocol of Step Cof Preparation 22, using methyl 5-methoxy-3-oxovalerate.

¹H NMR (400 MHz, dmso-d6) δ ppm: 6.69 (wd, 1H), 6.31 (wd, 1H), 3.69 (s,3H), 3.59 (s, 3H), 3.49 (t, 2H), 3.2 (s, 3H), 3.11 (t, 2H)

Step B:6-[4-(Methoxycarbonyl)-5-(2-methoxyethyl)-1-methyl-1H-pyrrol-2-yl]-1,3-benzo-dioxole-5-carboxylicAcid

The procedure is in accordance with the protocol described in Steps Band C of Preparation 1, replacing the 2-bromo-4-chlorobenzaldehyde usedin Step B by 6-bromo-1,3-benzodioxole-5-carbaldehyde.

Preparation 25:2-[4-(Ethoxycarbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]benzoic Acid

The procedure is in accordance with the process of Preparation 1,replacing the 2-bromo-4-chlorobenzaldehyde used in Step B by2-bromobenzaldehyde.

¹H NMR (400 MHz, dmso-d6) δ ppm: 12.81 (m, 1H), 7.84 (m, 1H), 7.59 (m,1H), 7.51 (m, 1H), 7.35 (m, 1H), 6.23 (s, 1H), 4.16 (q, 2H), 3.24 (s,3H), 2.5 (s, 3H), 1.25 (t, 3H)

Preparation 26:5-Fluoro-2-[4-(methoxycarbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-benzoicAcid

The procedure is in accordance with the process of Preparation 1,replacing in Step A the ethyl 2-methyl-1H-pyrrole-3-carboxylate bymethyl 2-methyl-1H-pyrrole-3-carboxylate and also the2-bromo-4-chlorobenzaldehyde used in Step B by2-bromo-5-fluoro-benzaldehyde.

¹H NMR (400 MHz, dmso-d6) δ ppm: 7.6 (dd, 1H), 7.42 (m, 2H), 6.22 (s,1H), 4.15 (q, 2H), 3.21 (s, 3H), 2.5 (s, 3H), 1.23 (t, 3H)

¹⁹F NMR (400 MHz, dmso-d6) δ ppm: −113

Preparation 27:2-[4-(Ethoxycarbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-5-fluoro-4-methoxybenzoicAcid

The procedure is in accordance with the process of Preparation 1,replacing in Step A the ethyl 2-methyl-1H-pyrrole-3-carboxylate bymethyl 2-methyl-1H-pyrrole-3-carboxylate and also the2-bromo-4-chlorobenzaldehyde used in Step B by2-bromo-4-methoxy-5-fluorobenzaldehyde.

¹H NMR (400 MHz, dmso-d6) δ ppm: 9.65 (d, 1H), 7.67 (d, 1H), 7.24 (d,1H), 6.48 (s, 1H), 4.19 (q, 2H), 3.97 (s, 3H), 3.38 (s, 3H), 2.56 (s,3H), 1.26 (t, 3H).

Preparation 28:2-(4-Ethoxycarbonyl-1,5-dimethyl-1H-pyrrol-2-yl)-4-fluoro-5-methoxybenzoicAcid

The procedure is in accordance with Preparation 1, replacing the2-bromo-4-chlorobenzaldehyde used in Step B by4-fluoro-5-methoxybenzaldehyde.

¹H NMR (400 MHz, dmso-d6) δ ppm: 12.9 (m, 1H), 7.6 (d, 1H), 7.22 (d,1H), 6.23 (s, 1H), 4.2 (quad, 2H), 3.95 (s, 3H), 3.25 (s, 3H), 2.5 (s,3H), 1.25 (t, 3H)

Preparation 29:5-Chloro-2-[4-(ethoxycarbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]benzoic Acid

The procedure is in accordance with the process of Preparation 1,replacing the 2-bromo-4-chlorobenzaldehyde used in Step B by2-bromo-5-chlorobenzaldehyde.

Preparation 30:2-{1-[2-(Benzyloxy)ethyl]-4-(ethoxycarbonyl)-5-methyl-1H-pyrrol-2-yl}-4-chlorobenzoicAcid

The procedure is in accordance with the process of Preparation 19,replacing the 6-bromo-1,3-benzodioxole-5-carbaldehyde by2-bromo-4-chlorobenzaldehyde.

Preparation 31:5-Methoxy-2-[4-(methoxycarbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]-benzoicAcid

The procedure is in accordance with the process of Preparation 1,replacing in Step A the ethyl 2-methyl-1H-pyrrole-3-carboxylate bymethyl 2-methyl-1H-pyrrole-3-carboxylate and also the2-bromo-4-chlorobenzaldehyde used in Step B by2-bromo-5-methoxy-benzaldehyde.

¹H NMR (400 MHz, dmso-d6) δ ppm: 12.8 (bs, 1H), 7.34 (wd, 1H), 7.26 (d,1H), 7.15 (dd, 1H), 6.19 (s, 1H), 3.84 (s, 3H), 3.69 (s, 3H), 3.22 (s,3H), 2.5 (s, 3H)

Preparation 32:6-[1-(2,2-Difluoroethyl)-4-(ethoxycarbonyl)-5-methyl-1H-pyrrol-2-yl]-1,3-benzodioxole-5-carboxylicAcid

The procedure is in accordance with the protocol of Preparation 19,replacing the 2-bromoethoxymethylbenzene used in Step A by2-bromo-1,1-difluoro-ethane.

Preparation 1′: (3R)-3-Methyl-1,2,3,4-tetrahydroisoquinolinehydrochloride Step A:{(3S)-2-[(4-Methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisoquinolin-3-yl}methyl4-methylbenzenesulphonate

To a solution of 30.2 g of[(3S)-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol (185 mmol) in 750 mLof dichloromethane there are successively added 91.71 g of tosylchloride (481 mmol) and then, dropwise, 122.3 mL of N,N,N-triethylamine(740 mmol). The reaction mixture is then stirred at ambient temperaturefor 20 hours. It is then diluted with dichloromethane, washedsuccessively with 1M HCl solution, saturated aqueous NaHCO₃ solution andthen brine until neutral. The organic phase is then dried over MgSO₄,filtered and concentrated to dryness. The solid obtained is thendissolved in a minimum volume of dichloromethane and then cyclohexane isadded until a precipitate is formed. This precipitate is then filteredoff and washed with cyclohexane. After drying, the title product isobtained in the form of crystals.

¹H NMR: δ (400 MHz; dmso-d6; 300K): 7.75 (d, 2H, aromatic Hs, ortho0-tosyl); 7.6 (d, 2H, aromatic Hs, ortho N-tosyl); 7.5 (d, 2H, aromaticHs, meta O-tosyl); 7.3 (d, 2H, aromatic Hs, meta N-tosyl); 7.15-6.9 (m,4H, aromatic Hs, tetrahydroisoquinoline); 4.4-4.15 (dd, 2H, aliphaticHs, tetrahydroisoquinoline); 4.25 (m, 1H, aliphatic H,tetrahydroisoquinoline); 4.0-3.8 (2dd, 2H, aliphatic Hs, CH₂—O-tosyl);2.7 (2dd, 2H, aliphatic Hs, tetrahydroisoquinoline); 2.45 (s, 3H,O—SO₂-Ph-CH₃); 2.35 (s, 3H, N—SO₂-Ph-CH₃)

IR: ν: —SO₂: 1339-1165 cm⁻¹

Step B:(3R)-3-Methyl-2-[(4-methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisoquinoline

To a suspension of 8.15 g (214.8 mmol) of lithium aluminium hydride(LiAlH₄) in 800 mL of methyl tert-butyl ether (MTBE) there are added101.2 g of the ditosyl compound obtained in Step A (214.8 mmol)dissolved in 200 mL of MTBE. The batch is then heated at 50° C. for 2hours. It is allowed to cool and placed at 0° C., and there are thenadded, dropwise, 12 mL of 5N NaOH solution. The batch is stirred atambient temperature for 45 minutes. The solid thereby obtained is thenfiltered off and washed with MTBE and then with dichloromethane. Thefiltrate is then concentrated to dryness. The title product is thenobtained in the form of a solid.

¹H NMR: δ (400 MHz; dmso-d6; 300K): 7.70 (d, 2H, aromatic Hs, orthoN-tosyl); 7.38 (d, 2H, aromatic Hs, meta N-tosyl); 7.2-7.0 (m, 4H,aromatic Hs, tetrahydroisoquinoline); 4.4 (m, 2H, aliphatic Hs,tetrahydroisoquinoline); 4.3 (m, 1H, aliphatic H,tetrahydroisoquinoline); 2.85-2.51 (2dd, 2H, aliphatic Hs,tetrahydroisoquinoline); 2.35 (s, 3H, N—SO₂-Ph-CH₃); 0.90 (d, 3H,tetrahydroisoquinoline-CH₃)

IR: ν: —SO₂: 1332-1154 cm⁻¹

Step C: (3R)-3-Methyl-1,2,3,4-tetrahydroisoquinoline

To a solution of 31.15 g (103.15 mmol) of the monotosyl compoundobtained in Step B in 500 mL of anhydrous methanol there are added, inportions, 3.92 g (161 mmol) of magnesium turnings. The batch is stirredin the presence of ultrasound for 96 hours. The reaction mixture is thenfiltered and the solid is washed several times with methanol. Thefiltrate is then concentrated to dryness. After purification bychromatography over silica gel using dichloromethane andammonia-in-ethanol as eluants, the title product is obtained in the formof an oil.

¹H NMR: δ (400 MHz; dmso-d6; 300K): 7.05 (m, 4H, aromatic Hs,tetrahydroisoquinoline); 3.90 (m, 2H, aliphatic Hs,tetrahydroisoquinoline); 2.85 (m, 1H, aliphatic H,tetrahydroisoquinoline); 2.68-2.4 (2dd, 2H, aliphatic Hs,tetrahydroisoquinoline); 1.12 (d, 3H, tetrahydroisoquinoline-CH₃);2.9-2.3 (m, broad, 1H, HN (tetrahydroisoquinoline))

IR: ν: —NH: 3248 cm⁻¹

Step D: (3B)-3-Methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride

To a solution of 14.3 g (97.20 mmol) of the compound obtained in Step Cin 20 mL of anhydrous ethanol there are added, dropwise, 100 mL of a 1Msolution of HCl in ether. The batch is stirred at ambient temperaturefor 1 hour and then filtered. The crystals thereby obtained are washedwith ethyl ether. After drying, the title product is obtained in theform of crystals.

¹H NMR: δ (400 MHz; dmso-d6; 300K): 9.57 (m, broad, 2H, NH₂ ⁺(tetrahydro-isoquinoline); 7.22 (m, 4H, aromatic Hs,tetrahydroisoquinoline); 4.27 (s, 2H, aliphatic Hs,tetrahydroisoquinoline); 3.52 (m, 1H, aliphatic H,tetrahydroisoquinoline); 3.03-2.85 (2dd, 2H, aliphatic Hs,tetrahydroisoquinoline); 1.39 (d, 3H, tetrahydroisoquinoline-CH₃)

IR: ν: —NH₂ ⁺: 3000-2300; ν: aromatic —CH: 766 cm⁻¹

Preparation 2′: tert-Butyl[(3S)-1,2,3,4-tetrahydroisoquinolin-3-ylmethyl]-carbamate Step A: Benzyl(3S)-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

This compound is obtained using a protocol from the literature (R. B.Kawthekar et al South Africa Journal of Chemistry 63, 195, 2009)starting from 15 g of (3S)-1,2,3,4-tetrahydroisoquinolin-3-ylmethanol(91.9 mmol) in the presence of benzyl chloroformate and triethylamine insolution in dichloromethane. After purification by chromatography oversilica gel using petroleum ether and ethyl acetate as eluants, the titleproduct is obtained in the form of an oil.

¹H NMR: δ (300 MHz; DMSO-d6; 300K): 7.33 (m, 5H, aromatic Hs, O-benzyl);7.15 (s, 4H, aromatic Hs, H tetrahydroisoquinoline); 5.13 (s, 2H,CH₂-Ph); 4.73 (d, 1H, H tetrahydroisoquinoline); 4.47 (m, H, CH₂OH);4.36 (m, 1H, H tetrahydroisoquinoline); 4.28 (d, 1H, Htetrahydroisoquinoline); 3.39 (dd, 1H, CH₂OH); 3.23 (dd, 1H CH₂OH); 2.93(dd, 1H, H tetrahydroisoquinoline); 2.86 (dd, 1H, Htetrahydroisoquinoline)

IR: ν: OH: 3416 cm⁻¹; ν: <C═O 1694 cm⁻¹ ν: aromatic >C—H: 754 cm⁻¹

Step B: Benzyl(3S)-3-(azidomethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

This compound is obtained using a protocol from the literature (D. Pagéet al J. Med. Chem, 44, 2387, 2001) starting from 23 g of the compoundobtained in Step A (77.3 mmol) in the presence of diphenylphosphorylazide and triphenylphosphine in solution in THF. After purification bychromatography over silica gel using petroleum ether and ethyl acetateas eluants, the title product is obtained in the form of an oil.

¹H NMR: δ (400 MHz; DMSO-d6; 300K): 7.36 (m, 5H, aromatic Hs, O-benzyl);7.19 (m, 4H, aromatic Hs, H tetrahydroisoquinoline); 5.16 (s, 2H,CH₂-Ph); 4.76 (d, 1H, H tetrahydroisoquinoline); 4.53 (m, 1H, Htetrahydroisoquinoline); 4.30 (m, 1H, H tetrahydroisoquinoline); 3.28(m, 2H, CH₂N₃); 3.06 (dd, 1H, H tetrahydroisoquinoline); 2.78 (dd, 1H, Htetrahydroisoquinoline)

IR: ν: N₃: 2095 cm⁻¹; ν: <C═O: 1694 cm⁻¹; ν: aromatic >C—H: 754 cm⁻¹

Step C: Benzyl(3S)-3-(aminomethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of 20.9 g (64.5 mmol) of the azido compound obtained inStep B in 650 mL of THF, there are successively added 25.5 g (97.2 mmol)of triphenylphosphine and 157 mL of water. The batch is refluxed for 2hours 30 minutes. The reaction mixture is then concentrated to drynessand the residue oil is then taken up in isopropyl ether. A whiteprecipitate appears; it is filtered off and washed with isopropyl ether.The filtrate is then concentrated to dryness and then purified bychromatography over silica gel using dichloromethane and methanol aseluants. The title product is obtained in the form of an oil.

¹H NMR: δ (400 MHz; DMSO-d6; 300K): 7.40 (m, 5H, aromatic Hs, O-benzyl);7.20 (m, 4H, aromatic Hs, H tetrahydroisoquinoline); 5.15 (s, 2H,CH₂-Ph); 4.75-4.3 (m, 2H, H tetrahydroisoquinoline); 4.30 (d, 1H, Htetrahydroisoquinoline); 2.90 (m, 2H, CH₂NH₂); 2.45 (m, 2H, Htetrahydroisoquinoline); 1.40 (m, 2H, NH₂)

IR: ν: NH₂: 3400-3300 cm⁻¹; ν: <C═O: 1688 cm⁻¹

Step D: Benzyl(3S)-3-{[(tert-butoxycarbonyl)amino]methyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of 18.4 g (62.1 mmol) of the compound obtained in Step Cin 630 mL of dichloromethane there are successively added 17.5 mL (124mmol) of triethylamine and, in portions, 14.9 g (68.3 mmol) ofdi-tert-butyl dicarbonate. The batch is stirred at ambient temperaturefor 2 h. The reaction mixture is then concentrated and ethyl acetate isthen added. The organic phase is successively washed with 1M HClsolution, brine, saturated aqueous NaHCO₃ solution and then brine. Afterdrying, concentrating to dryness and purifying by chromatography oversilica gel using petroleum ether and ethyl acetate as to eluants, thetitle product is obtained in the form of an oil.

¹H NMR: δ (400 MHz; DMSO-d6; 300K): 7.35 (m, 5H, aromatic Hs, O-benzyl);7.15 (m, 4H, aromatic Hs, H tetrahydroisoquinoline); 6.51 (m, 1H,NHBoc); 5.12 (s, 2H, CH₂-Ph); 4.76 (d, 1H, H tetrahydroisoquinoline);4.51 (m, 1H, H tetrahydroisoquinoline); 4.36 (d, 1H, Htetrahydroisoquinoline); 2.95 (m, 3H, Htetrahydroisoquinoline+CH₂NHBoc); 2.71 (d, 1H, Htetrahydroisoquinoline); 1.34 (s, 9H, NHBoc)

IR: ν: NH: 3351 cm⁻¹; ν: <C═O: 1686 cm⁻¹

Step E: tert-Butyl[(3S)-1,2,3,4-tetrahydroisoquinolin-3-ylmethyl]carbamate

To a solution of 21 g (53 mmol) of the compound obtained in Step D in600 mL of ethyl acetate there are added 2.1 g of palladium-on-carbon10%. The batch is stirred at ambient temperature under a pressure of 1.3bars of dihydrogen for 5 hours. The reaction mixture is then filteredand then concentrated to dryness. The title product is obtained in theform of a solid.

¹H NMR: δ (400 MHz; DMSO-d6; 300K): 7.15 (m, 4H, aromatic Hs, Htetrahydro-isoquinoline); 6.85 (t, 1H, NHBoc); 3.90 (m, 2H, Htetrahydroisoquinoline); 3.00 (m, 2H, CH₂NHBoc); 2.80 (m, 1H, Htetrahydroisoquinoline); 2.65 (dd, 1H, H tetrahydro-isoquinoline); 2.40(dd, 1H, H tetrahydroisoquinoline); 1.40 (s, 9H, NHBoc)

IR: ν: NH: 3386-3205 cm⁻¹ (NH amide); ν: <C═O: 1688 cm⁻¹; ν: NH: 1526cm⁻¹ (NH amine)

Preparation 3′:(3S)-3-(4-Morpholinylmethyl)-1,2,3,4-tetrahydroisoquinoline Step A:Benzyl(3S)-3-(4-morpholinylcarbonyl)-3,4-dihydro-2(1H)-isoquinoline-carboxylate

To a solution of 5 g of(3S)-2-[(benzyloxy)carbonyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid (16 mmol) in 160 mL of dichloromethane there are added 1.5 mL ofmorpholine (17.6 mmol), then 9 mL of N,N,N-triethylamine (64 mmol), 3.3g of 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (EDC) (19.2 mmol)and 2.6 g of hydroxybenzotriazole (HOBt) (19.2 mmol). The reactionmixture is stirred at ambient temperature overnight; it is then pouredinto ammonium chloride solution and extracted with ethyl acetate. Theorganic phase is then dried over MgSO₄, and then filtered and evaporatedto dryness. The crude product thereby obtained is then purified bychromatography over silica gel using dichloromethane and methanol aseluants. The product is obtained in the form of a foam.

¹H NMR: δ (400 MHz; dmso-d6; 353K): 7.30 (m, 5H benzyl); 7.15 (m, 4H,aromatic Hs); 5.2-5.0 (m, 3H, 2H benzyl, 1H dihydroisoquinoline);4.75-4.5 (2d, 2H dihydroisoquinoline); 3.55-3.3 (m, 8H morpholine);3.15-2.9 (2dd, 2H dihydroisoquinoline)

IR: ν: >C═O: 1694; 1650 cm⁻¹

Step B: Benzyl(3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate

To a solution of 5.3 g of the product obtained in Step A (13.9 mmol) in278 mL of tetrahydrofuran there are added 14 mL ofborane-dimethylsulphide complex (BH₃Me₂S) (27.8 mmol) at ambienttemperature. The batch is heated for 4 hours at 80° C. It is allowed toreturn to ambient temperature and there are then added 7 mL (14 mmol) ofBH₃Me₂S. The reaction mixture is again heated at 80° C. for 2 hours. Thetetrahydrofuran is then evaporated off and then there is slowly addedmethanol and then 5.6 mL of 5N aqueous HCl solution (27.8 mmol). Themixture is stirred at ambient temperature overnight, and then at 80° C.for 1 hour. Saturated aqueous NaHCO₃ solution is then added to thereaction mixture placed at 0° C. until a pH of 8 is obtained, andextraction with ethyl acetate is then carried out. The organic phase isthen dried over MgSO₄, and then filtered and evaporated to dryness. Thetitle product is obtained in the form of an oil.

¹H NMR: δ (400 MHz; dmso-d6; 353K): 7.43-7.30 (unresolved peak, 5Hbenzyl); 7.19 (m, 4H, aromatic Hs); 5.16 (m, 2H, 2H benzyl); 4.79-4.29(d, 2H dihydroisoquinoline); 4.58 (m, 1H dihydroisoquinoline); 3.50 (m,4H morpholine); 3.02-2.80 (dd, dihydroisoquinoline); 2.42-2.28(unresolved peak, 5H, 4H morpholine, 1H morpholine); 2.15 (dd, 1Hmorpholine)

IR: ν: >CH: 2810 cm⁻¹; ν: >C═O: 1694 cm⁻¹; ν: >C—O—C<: 1114 cm⁻¹;ν: >CH—Ar: 751; 697 cm⁻¹

Step C: (3S)-3-(4-Morpholinylmethyl)-1,2,3,4-tetrahydroisoquinoline

To a solution of 4.9 g of the compound of Step B (13.4 mmol) in 67 mL ofethanol there is added 0.980 g of palladium dihydroxide (20% by weight)at ambient temperature. The reaction mixture is placed under 1.2 bars ofhydrogen at ambient temperature for 4 hours. It is then passed through aWhatman filter and the palladium is then rinsed several times withethanol. The filtrate is evaporated to dryness. The title product isobtained in the form of an oil.

¹H NMR: δ (400 MHz; dmso-d6; 300K): 7.12-7.0 (unresolved peak, 4H,aromatic Hs); 3.92 (s, 2H tetrahydroisoquinoline); 3.60 (t, 4Hmorpholine); 2.98 (m, 1H tetrahydroisoquinoline); 2.68 (dd, 1Htetrahydroisoquinoline); 2.5-2.3 (unresolved peak, 8H, 11-1tetrahydroisoquinoline, 61-1 morpholine, 1H NH)

IR: ν: >NH: 3322 cm⁻¹; ν: >C—O—C<: 1115 ν: >CH—Ar: 742 cm⁻¹

Preparation 4′:(3S)-3-[(4-Methyl-1-piperazinyl)methyl]-1,2,3,4-tetrahydro-isoquinoline

The procedure is in accordance with the process of Preparation 3′,replacing the morpholine used in Step A by 1-methyl-piperazine.

Preparation 5′:(3S)-3-[2-morpholin-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride Step A: tert-Butyl(3S)-3-(2-morpholino-2-oxo-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

To a solution of 3 g (10.3 (mmol) of[(3S)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]aceticacid in 100 mL of dichloromethane, there are added dropwise 1.10 mL(11.32 mmol) of morpholine, still dropwise 4.3 mL (30.9 mmol) oftriethylamine, 2.20 g (12.40 mmol) of EDC and 1.70 g (1.68 mmol) of HOBt(hydroxybenzotriazole). The batch is stirred at ambient temperature for15 hours. The reaction mixture is then diluted with dichloromethane,successively washed with 1M HCl solution, saturated aqueous NaHCO₃solution and then brine until neutral. The organic phase is then driedover MgSO₄, filtered and concentrated to dryness. After purification bychromatography over silica gel using dichloromethane and methanol aseluants, the title product is obtained in the form of an oil.

¹H NMR: δ (400 MHz; dmso-d6; 300K): 7.20-7.10 (m, 4H, aromatic Hs,tetrahydroisoquinoline); 4.70 (m, 1H, aliphatic Hs, CHtetrahydroisoquinoline); 4.75-4.20 (2m, 2H, aliphatic Hs, CH₂ alpha to Ntetrahydroisoquinoline); 3.60 (m, 8H, aliphatic Hs, morpholine); 3.00and 2.70 (2dd, 2H, aliphatic H, tetrahydroisoquinoline); 2.50-2.20 (2d,2H, aliphatic Hs, CH₂CO); 1.40 (s, 9H, ^(t)Bu)

IR: ν: C═O: 1687; 1625 cm⁻¹

Step B:1-(Morpholin-4-yl)-2-[(3S)-1,2,3,4-tetrahydroisoquinolin-3-yl]ethanonehydrochloride

To a solution of 2.88 g (7.18 mmol) of the compound obtained in Step Ain 16 mL of dichloromethane, there are added dropwise 80 mL (80 mmol) of1M solution of HCl in ether. The batch is stirred at ambient temperaturefor 15 hours, and then the suspension is filtered and the precipitatewashed with ether. After drying, the title product is obtained in theform of a solid.

¹H NMR: δ (400 MHz; dmso-d6; 300K): 9.80-9.50 (m, 2H, NH₂ ⁺); 7.30-7.10(m, 4H, aromatic Hs, tetrahydroisoquinoline); 4.30 (m, 2H, aliphatic Hs,CH₂ alpha to N tetrahydroisoquinoline); 3.80 (m, 1H, aliphatic Hs, CHtetrahydroisoquinoline); 3.70-3.40 (2m, 8H, aliphatic Hs, morpholine);3.15 and 2.8 (m, 4H, aliphatic H, CH₂ tetrahydroisoquinoline and CH₂CO)

IR: ν: —NH₂ ⁺: 2800-1900 cm⁻¹, ν: C═O: 1620 cm⁻¹

Step C: (3S)-3-[2-(Morpholin-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride

A solution of 2.2 g (7.44 mmol) of the compound obtained in Step B in 22mL of MTBE and 5 mL of dichloromethane is prepared. After cooling in anice bath at 0° C., there are added thereto, dropwise, 15 mL (15 mmol) of1 M LiAlH₄ solution in tetrahydrofuran. The batch is then stirred atambient temperature for 6 hours. It is placed at 0° C., and there isthen added, dropwise, 1 mL of 5N NaOH solution. The batch is stirred atambient temperature for 45 minutes. The solid is then filtered off andwashed with MTBE and then with dichloromethane and the filtrate isconcentrated to dryness. The oil thereby obtained is diluted withdichloromethane and there are added, dropwise, 6.3 mL of a 1M solutionof HCl in ether. The batch is stirred at ambient temperature for 1 hourand then filtered. The crystals thereby obtained are washed with ethylether. After drying, the title product is obtained in the form of asolid.

¹H NMR: δ (400 MHz; dmso-d6; 300K): 11.35+9.80 (2m, 2H, NH₂ ⁺); 10.00(m, H, NH⁺); 7.20 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 4.30 (s,2H, aliphatic Hs, CH₂ alpha to N tetrahydroisoquinoline); 4.00+3.85 (2m,4H, aliphatic Hs, CH₂ alpha to N morpholine); 3.70 (m, 1H, aliphatic Hs,CH tetrahydroisoquinoline); 3.55-3.30 (m, 4H, aliphatic Hs, CH alpha to0 morpholine and CH₂-morpholine); 3.15 (dd, 1H, aliphatic H, CH₂tetrahydroisoquinoline); 3.10 (m, 2H, aliphatic H, CH alpha to 0morpholine); 2.90 (dd, 1H, aliphatic H, CH₂ tetrahydroisoquinoline);2.30+2.15 (2m, 2H, aliphatic H, CH₂-tetrahydroisoquinoline)

IR: ν: NH⁺/—NH₂ ⁺: between 3500 and 2250 cm⁻¹: ν: C═C: weak 1593 cm⁻¹:ν: aromatic C—H: 765 cm⁻¹

Preparation 6′:(3R)-3-[3-(Morpholin-4-yl)propyl]-1,2,3,4-tetrahydroisoquinoline Step A:{(3S)-2-[(4-Methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisoquinolin-3-yl}methyl4-methylbenzenesulphonate

The process is the same as that of Step A of Preparation 1′.

Step B: tert-Butyl2-({(3R)-2-[(4-methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisaquinolin-3-yl}methyl)-3-(morpholin-4-yl)-3-oxopropanoate

To a suspension of 1 g of NaH (60%) (25.08 mmol) in 30 mL of MTBE thereare added, dropwise, a solution of 5 g of tert-butyl3-morpholino-3-oxopropanoate (21.81 mmol) in 20 mL of anhydrous MTBE.This suspension stirred at ambient temperature for 1 hour and then thecompound obtained in Step A is added in the form of a powder. The batchis stirred at 60° C. for 30 hours. 100 mL of saturated aqueous ammoniumchloride solution are added. The resulting solution is extracted withdichloromethane. The organic phase is then dried over MgSO₄, filteredand concentrated to dryness. After purification by chromatography oversilica gel using dichloromethane and MeOH as eluants, the expectedproduct is obtained in the form of an oil.

¹H NMR (500 MHz, dmso-d6) δ ppm: 7.63/7.59 (2d, 2H), 7.3/7.26 (2d, 2H),7.13 (m, 2H), 7.09/6.97 (2t, 2H), 4.64/4.55/4.36/4.28 (2AB, 2H),4.25/4.11 (2m, 1H), 3.81 (m, 1H), 3.73-3.48 (m, 4H), 3.57-3.32 (m, 4H),2.51 (m, 2H), 2.32/2.31 (2s, 3H), 1.88/1.79 (2m, 2H), 1.39/1.38 (2s, 9H)

IR (ATR) cm⁻¹: ν: >C═O: 1731 (ester); ν: >C═O: 1644 (amide); ν: —SO2:1334-1156; ν: >C—O—C: 1115; γ: >CH—Ar: 815-746-709

Step C:2-({(3R)-2-[(4-Methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisoquinolin-3-yl}methyl)-3-(morpholin-4-yl)-3-oxopropanoicAcid

To a solution of 9.5 g (17.97 mmol) of the compound obtained in Step Bin 40 mL of dioxane there are added, dropwise, 20 mL of a 4M solution ofHCl in dioxane. The batch is stirred at ambient temperature for 48 hoursand then the solution is concentrated to dryness. After drying, theexpected product is obtained in the form of an oil.

¹H NMR (400 MHz, dmso-d6) δ ppm: 12.75 (m, 1H), 7.6 (2*d, 2H), 7.3 (2*d,2H), 7.1/6.95 (2*m, 4H), 4.7-4.2 (d, 2H), 4.25/4.12 (2*m, 1H), 3.9-3.3(m, 9H), 2.55 (d, 2H), 2.3 (2*s, 3H), 1.8 (t, 2H)

IR (ATR) cm⁻¹: ν: —OH: 3500 to 2000: ν: >C═O: 1727 (acid); ν: 1634(amide); ν: —SO2: 1330-1155

Step D:3-{(3R)-2-[(4-Methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisoquinolin-3-yl}-1-(morpholin-4-yl)propan-1-one

To a solution of 7.80 g (16.51 mmol) of the compound obtained in Step Cin 100 mL of DMSO there are added 1.16 g (19.83 mmol) of solid sodiumchloride (NaCl) and then, to dropwise, 5 mL of water. The batch isstirred at 130° C. for 1 hour and then the solution is concentrated to¾. The reaction mixture is then diluted with dichloromethane and washedsuccessively with saturated aqueous lithium chloride solution and thenwith brine. The organic phase is then dried over MgSO₄, filtered andconcentrated to dryness. After purification by chromatography oversilica gel using cyclohexane and ethyl acetate as eluants, the expectedproduct is obtained in the form of an oil.

¹H NMR (400 MHz, dmso-d6) δ ppm: 7.65 (d, 2H), 7.3 (d, 2H), 7.15/7 (2 m,4H), 4.6 (d, 1H), 4.25 (d, 1H), 4.2 (m, 1H), 3.5 (m, 4H), 3.4 (2 m, 4H),2.6 (2 dd, 2H), 2.35 (s, 3H), 2.3 (m, 2H), 1.5 (quad., 2H)

IR (ATR) cm⁻¹: ν: >C═O: 1639; ν: —SO2: 1331-1156; γ: >CH—Ar: 815-675

Step E:(3R)-2-[(4-Methylphenyl)sulphonyl]-3-[3-(morpholin-4-yl)propyl]-1,2,3,4-tetrahydroisoquinoline

To a solution of 6.0 g (14.0 mmol) of the compound obtained in Step D in60 mL of MTBE and 14 mL of dichloromethane there are added 1.06 g (28mmol) of LAH in portions over 5 minutes. The batch is stirred at ambienttemperature for 15 hours. There are added, dropwise, 1.5 mL of water andstirring is carried out for 15 minutes. There are then added, dropwise,1.5 mL of 5M sodium hydroxide solution and stirring is carried out for15 minutes. The reaction mixture is then diluted with MTBE anddichloromethane. The suspension is then filtered and the precipitate iswashed with MTBE and dichloromethane. The organic phase is then driedover MgSO₄, filtered and concentrated to dryness. After purification bychromatography over silica gel using dichloromethane andammonia-in-ethanol as eluants, the expected product is obtained in theform of an oil.

¹H NMR (400 MHz, dmso-d6) δ ppm: 7.68 (d, 2H), 7.32 (d, 2H), 7.1(unresolved peak, 4H), 4.65/4.23 (AB, 2H), 4.2 (m, 1H), 3.55 (t, 4H),2.7/2.6 (ABX, 2H), 2.35 (s, 3H), 2.25 (t, 4H), 2.2 (t, 2H), 1.4/1.3 (2m,4H).

IR (ATR) cm⁻¹: ν: —SO2: 1333-1158

Step F: (3R)-3-[3-(Morpholin-4-yl)propyl]-1,2,3,4-tetrahydroisoquinoline

To a solution of 1.50 g (3.62 mmol) of the compound obtained in Step Ein 20 mL of anhydrous methanol there are added 2.0 g (82.3 mmol), inportions, of magnesium turnings. The batch is stirred in the presence ofultrasound for 96 hours. The reaction mixture is then filtered, thesolid is washed several times with methanol, and the filtrate isconcentrated to dryness. After purification by chromatography oversilica gel using dichloromethane and ammonia-in-ethanol as eluants, theexpected product is obtained in the form of an oil.

¹H NMR (400 MHz, dmso-d6) δ ppm: 7.3 (d, 2H), 7.1 (t, 2H), 7.1 (d+t,3H), 7 (d, 2H), 3.9 (s, 2H), 3.55 (t, 4H), 2.75 (m, 1H), 2.72/2.45 (dd,2H), 2.35 (t, 4H), 2.25 (t, 2H), 1.6 (m, 2H), 1.45 (m, 2H)

IR (ATR) cm⁻¹: ν: >NH2+/NH+: 3500-2300; ν: >C—O—C<: 1115

High-resolution mass spectrometry (ESI+−/FIA/HR):

Empirical formula: C₁₆H₂₄N₂O

[M+H]⁺ calculated: 261.1961

[M+H]⁺ measured: 261.1959

Preparation 7′:(3S)-3-[(9aS)-Octahydropiperazino[2,1-c]morpholin-8-ylmethyl]-1,2,3,4-tetrahydroisoquinolinetrihydrochloride Step A: tert-Butyl(9aS)-4-oxo-octahydropiperazino[2,1-c]morpholine-8-carboxylate

The synthesis of this compound is known in the literature (J. Med. Chem.2012, 55, 5887 for the opposite enantiomer).

Step B: (9aS)-Octahydropiperazino[2,1-c]morpholin-4-one hydrochloride

A 4M solution of HCl in dioxane (60 mL, 240 mmol) is added to thecompound tert-butyl(9aS)-4-oxo-octahydropiperazino[2,1-c]morpholine-8-carboxylate (11.8 g,46.0 mmol) cooled using an ice bath. The solution is then stirred atambient temperature for 2 hours, and then at 50-60° C. for 1.5 hours.The solution is then evaporated to dryness. The residue is co-evaporatedwith dioxane (3×20 mL) and then dried in vacuo to obtain the expectedcompound in the form of a solid.

¹H NMR (400 MHz, dmso-d6) δ ppm: 2.80-2.94 (m, 2H), 2.94-3.05 (m, 1H),3.23-3.37 (m, 2H), 3.59-3.69 (m, 1H), 3.83-3.93 (m, 1H), 3.95-4.04 (m,1H), 4.02-4.13 (m, 2H), 4.45-4.55 (m, 1H), 9.58 (br s, 2H)

Step C: tert-Beryl(3S)-3-[(9aS)-4-oxo-octahydropiperazino[2,1-c]morpholine-8-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

EDC (3.90 g, 20.3 mmol) is added to a solution of the compound of Step B(3.02 g, 15.7 mmol),(3S)-2-[(tert-butoxy)carbonyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid (4.6 g, 16.6 mmol), triethylamine (8.0 mL, 57.4 mmol) and HOBt(2.72 g, 20.1 mmol) in dichloromethane (150 mL). The mixture is stirredat ambient temperature for 21 hours. 1N aqueous HCl solution (105 mL) isadded and the precipitate formed is filtered off using a Buchner funnel.The phases of the filtrate are separated. The aqueous phase is extractedwith dichloromethane (2×10 mL). The combined organic phases are washedwith 3N aqueous HCl solution (35 mL), then with aqueous 5% potassiumbicarbonate solution (2×35 mL) and finally with brine (35 mL). Theorganic phase is dried over Na₂SO₄, filtered and then concentrated underreduced pressure. The product is purified by chromatography over silicagel using ethyl acetate and heptane as eluants to obtain the expectedcompound in the form of a solid.

¹H NMR (400 MHz, CDCl₃) δ ppm: 1.38-1.57 (m, 9H), 2.39-2.89 (m, 2H),2.89-3.34 (m, 3H), 3.34-3.70 (m, 2H), 3.90-4.06 (m, 1H), 4.09-4.27 (m,2H), 4.30-5.00 (m, 5H), 5.20-5.37 (m, 1H), 7.03-7.24 (m, 4H)

Step D:(3S)-3-[(9aS)-Octahydropiperazino[2,1-c]morpholin-8-ylmethyl]-1,2,3,4-tetrahydroisoquinolinetrihydrochloride

4M HCl solution in dioxane (45 mL, 180 mmol) is added to the compound ofStep C (6.6 g, 46.0 mmol) cooled in an ice bath. The suspension is thenstirred at ambient temperature for 24 hours and then it is evaporated todryness. The residue is co-evaporated with MTBE and then dried in vacuo.The solid thereby obtained is suspended in tetrahydrofuran (160 mL), andthen LiAlH₄ (3.0 g, 79.1 mmol) is added. The suspension is refluxed for6.5 hours, and it is then cooled in an ice bath. Water (3 mL) is thenadded over a period of 7 minutes. After 0.5 hours, 2N aqueous sodiumhydroxide solution (6 mL) is added. Water (6 mL) is again added 0.25hours later. Finally, Celite (7 g) and Na₂SO₄ (25 g) are added 0.5 hourslater. The suspension is filtered over Celite and rinsed withtetrahydrofuran (2×100 mL). The filtrate is concentrated to dryness. Theoil thereby obtained is dissolved in MTBE (50 mL). The resultingsolution is filtered and the filtrate concentrated. The residue isdissolved in methanol (60 mL), and then 4M HCl solution in dioxane (20mL) is added. The solution is heated to 40° C. and treated withactivated charcoal (0.66 g), with stirring, for 1 hour. The suspensionis filtered over Celite and rinsed with warm methanol. The filtrate isconcentrated until the product starts to crystallise out.Crystallisation is allowed to continue for 16 hours at ambienttemperature. The solid obtained is filtered off and rinsed with amixture of 2-propanol/MTBE (4/6) (2×20 mL), and then with MTBE (2×20mL). After drying, the expected compound is obtained.

¹H NMR (400 MHz, D₂O) δ ppm: 2.28-2.44 (m, 1H), 2.74-3.00 (m, 4H),3.08-3.27 (m, 3H), 3.27-3.42 (m, 2H), 3.43-3.56 (m, 2H), 3.56-3.69 (m,2H), 3.76-3.95 (m, 2H), 4.00-4.22 (m, 2H), 4.35-4.50 (m, 2H), 7.20-7.41(m, 4H)

¹³C NMR (100 MHz, D₂O) δ ppm: 29.00, 44.58, 50.30, 51.08, 51.17, 52.75,53.17, 58.08, 61.60, 64.61, 66.37, 127.14, 127.71, 128.00, 128.77,129.55, 131.15 MS (ESI): [M+H]⁺ 288.16

Preparation 8′;(3S)-3-(1-Oxa-6-azaspiro[3,3]hept-6-ylmethyl)-1,2,3,4-tetrahydroisoquinolineStep A:(3S)-3-(Iodomethyl)-2-[(4-methylphenyl)sulphonyl]-1,2,3,4-tetrahydroisoquinoline

The compound of Step A of Preparation 6′ (4.0 g; 8.48 mmol) inacetonitrile (10 mL) is placed in a 27-ml microwave tube and then sodiumiodide (1.40 g; 9.33 mmol) is added. The reaction mixture is heated for5 hours at 100° C. using microwaves (200 W). It is then filtered and thesolid is washed with dichloromethane. The filtrate is evaporated todryness and then the residue is purified by chromatography over silicagel using heptane and ethyl acetate as eluants. The title compound isobtained in the form of an oil.

¹H NMR (400 MHz, dmso-d6) δ ppm: 7.64 (d, 2H), 7.28 (d, 2H), 7.15-7 (m,4H), 4.5/4.3 (2d, 2H), 4.14 (m, 1H), 3.22 (m, 2H), 2.82 (m, 2H), 2.31(s, 3H)

IR (ATR) cm⁻¹: 1897 ν —Ar, 1333+1156 ν —SO2

Step B:(3S)-2-[(4-Methylphenyl)sulphonyl]-3-(1-oxa-6-azaspiro[3,3]hept-6-ylmethyl)-1,2,3,4-tetrahydroisoquinoline

The iodinated compound (2.5 g; 5.85 mmol) obtained in the preceding Stepis dissolved in acetonitrile (50 mL). 1-Oxa-6-azaspiro[3.3]heptaneoxalate (1.21 g; 6.36 mmol) is added, followed by potassium carbonate(1.61 g; 11.7 mmol). The reaction mixture is heated for 15 hours atreflux. The reaction mixture is filtered and washed with acetonitrile,and then is evaporated to dryness.

The compound is purified by chromatography over silica gel usingdichloromethane and ammonia-in-methanol as eluants. The title compoundis obtained in the form of an oil.

¹H NMR (400 MHz, dmso-d6) δ ppm: 7.68 (d, 2H), 7.32 (d, 2H), 7.14-7 (m,4H), 4.53/4.2 (dd, 2H), 4.34 (t, 2H), 3.95 (m, 1H), 3.5/3.4/2.98 (3m,4H), 2.7 (t, 2H), 2.68-2.58 (m, 2H), 2.34 (s, 3H), 2.31-2.24 (m, 2H)

IR (ATR) cm⁻¹: 1333+1156 ν —SO2

Step C:(3S)-3-(1-Oxa-6-azaspiro[3.3]hept-6-ylmethyl)-1,2,3,4-tetrahydroisoquinoline

The tosylated compound of the above Step (1.3 g; 3.26 mmol) is dissolvedin 10 mL of methanol. Powdered magnesium (633 mg; 26.08 mmol) is addedin portions of 160 mg every 3 hours. The reaction mixture is stirred inan ultrasound bath 15 hours. It is then filtered over Celite, washedwith copious amounts of methanol, and then evaporated to dryness. Thecompound is purified by chromatography over silica gel usingdichloromethane and ammonia-in-methanol as eluants. The compound isobtained in the form of an oil.

¹H NMR (400 MHz, dmso-d6) δ ppm: 7.01 (m, 4H), 4.46 (t, 2H), 3.85 (s,2H), 3.51/3.05 to (dd, 2H), 2.73 (t, 2H), 2.61/2.4 (m, 4H), 2.4 (m, 1H),2.4 (m, 1H)

IR (ATR) cm⁻¹: 3325 ν>NH

Preparation 9′:(3S)-3-[(9aR)-Octahydropiperazino[2,1-c]morpholin-8-ylmethyl]-1,2,3,4-tetrahydroisoquinolinetrihydrochloride Step A: tert-Butyl(9aR)-4-oxo-octahydropiperazino[2,1-c]morpholine-8-carboxylate

Synthesis of this compound is described in the literature (J. Med. Chem.2012, 55, 5887).

Step B: (9aR)-Octahydropiperazino[2,1-c]morpholin-4-one hydrochloride

A 4M solution of HCl in dioxane (39 mL, 154 mmol) is added to thecompound of Step A (11.3 g, 44.1 mmol). The solution is then stirred atambient temperature for 5 hours, and then a 4M solution of HCl indioxane (12 mL, 48 mmol) is added again. The mixture is stirred for 16hours. The solution is then evaporated to dryness to yield the expectedproduct in the form of a solid.

¹H NMR (400 MHz, dmso-d6) δ ppm: 2.79-2.93 (m, 2H), 3.02 (td, J=13.1,2.7 Hz, 1H), 3.22-3.34 (m, 2H), 3.59-3.67 (m, 1H), 3.86-3.96 (m, 1H),3.96-4.01 (m, 1H), 4.05 (AB q, J=13.3 Hz, 2H), 4.48 (dd, J=14.1, 2.5 Hz,1H), 9.71 (br. s, 1H), 9.91 (br. s, 1H)

Step C: tert-Butyl(3S)-3-[(9aR)-4-oxo-octahydropiperazino[2,1-c]morpholine-8-carbonyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

EDC (5.17 g, 27.0 mmol) is added to a solution of the compound of theabove Step (4.0 g, 20.7 mmol),(3S)-2-[(tert-butoxy)carbonyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid (6.04 g, 21.8 mmol), triethylamine (11.6 mL, 83.1 mmol) and HOBt(3.65 g, 27.0 mmol) in dichloromethane (100 mL). The mixture is stirredat ambient temperature for 16 hours. 1N aqueous HCl solution (70 mL) isadded and the precipitate formed is filtered off using a Buchner funnel.The phases of the filtrate are separated. The organic phase is washedwith saturated aqueous potassium carbonate solution and is thenconcentrated under reduced pressure. The residue is pre-absorbed ontosilica gel and is purified by chromatography over silica gel using ethylacetate and heptane as eluants to yield the expected compound in theform of a solid.

¹H NMR (400 MHz, dmso-d6) δ ppm: 1.25-1.58 (m, 9H), 2.50-2.76 (m, 2H),2.76-3.25 (m, 3H), 3.37-3.76 (m, 2H), 3.92-4.50 (m, 5H), 4.06 (s, 2H),4.66 (d, J=15.6 Hz, 1H), 4.76-5.28 (m, 1H), 7.05-7.31 (n, 4H)

Step D:(3S)-3-[(9aR)-Octahydropiperazino[2,1-c]morpholin-8-ylmethyl]-1,2,3,4-tetrahydroisoquinolinetrihydrochloride

A 4M solution of HCl in dioxane (24.0 mL, 96.2 mmol) is added to asolution of the compound of Step C (8.00 g, 12.25 mmol) indichloromethane (25 mL). The mixture is stirred at ambient temperaturefor 16 hours and is then concentrated to dryness. The crude productobtained is added to a suspension of LiAlH₄ (1.97 g, 51.91 mmol) intetrahydrofuran (140 mL). The mixture is refluxed until the reaction(monitored by LC-MS) is complete and it is then cooled to 0° C. Water(2.5 mL) is added dropwise. After stirring for 10 minutes, aqueous 2Msodium hydroxide solution (5 mL) is added dropwise. Water (5 mL) isagain added after stirring for 10 minutes. There are finally addedCelite (4 g) and Na₂SO₄ (12 g) after stirring for an additional 10minutes. The suspension is filtered over Celite and the filtrate isconcentrated to dryness. The crude residue thereby obtained is dissolvedin methanol (80 mL), and then a 4M solution of HCl in dioxane (16.75 mL,67.0 mmol) is added. The mixture is stirred at ambient temperature for 3hours, and then concentrated to dryness. The residue is dissolved in aminimum of warm methanol (70 mL), and then MTBE (3-5 mL) is added. Thesolution is cooled at 0° C. for 1 hour in an ice-cold water bath, andthe product precipitates out. A little MTBE (2-3 mL) is again added andthe mixture is allowed to stand for a further 1 hour at 0° C. The solidobtained is filtered over a Buchner funnel and dried in vacuo to yieldthe expected compound in the form of a solid.

¹H NMR (400 MHz, CD₃OD) δ ppm: 2.65 (t, J=11.1 Hz, 1H), 2.74-2.97 (m,4H), 3.10 (d, J=12.5 Hz, 1H), 3.19 (dd, J=17.6, 4.8 Hz, 1H), 3.25-3.55(m, 5H), 3.59-3.74 (m, 2H), 3.82-4.15 (m, 4H), 4.45 (AB q, J=15.9 Hz,2H), 7.21-7.35 (m, 4H).

¹³C NMR (100 MHz, CD₃OD) δ ppm: 30.21, 45.67, 50.22, 51.99, 52.90,53.58, 53.71, 59.25, 62.58, 65.30, 67.07, 127.76, 128.40, 129.08,129.36, 130.16, 131.95

MS (ESI): [M+H]⁺ 288.2

Preparation 1″:N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-1-methyl-pyrazol-4-amine StepA: 4-{[tert-Butyl(dimethyl)silyl]oxy}aniline

The title compound is obtained starting from 4-aminophenol in THF in thepresence of imidazole and tert-butyl(dimethyl)silyl chloride inaccordance with the protocol described in the literature (S. Knaggs etal, Organic & Biomolecular Chemistry, 3(21), 4002-4010; 2005).

¹H NMR: δ (400 MHz; dmso-d6; 300K): 6.45-6.55 (dd, 4H, aromatic Hs);4.60 (m, 2H, NH2-Ph); 0.90 (s, 9H, Si (CH₂)₂CH(CH₃)₂); 0.10 (s, 6H, Si(CH₂)₂CH(CH₃)₂)

IR: ν: —NH₂ ⁺: 3300-3400 cm⁻¹

Step B:N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-1-methyl-pyrazol-4-amine

To a solution of 30.8 g (0.137 mol) of the compound of Step A in 525 mLof anhydrous toluene there are successively added 29.8 g of sodiumtert-butylate (0.310 mol), 4.55 g of Pd₂(dba)₃ (also referred to astris(dibenzylideneacetone)dipalladium(0)) (4.96 mmol), 4.81 g of2-di-tert-butylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (9.91mmol) and 12.8 mL of 4-bromo-1-methyl-1H-pyrazole (0.124 mol). The batchis degassed under argon for 30 minutes and then refluxed for 3 hours. Itis allowed to cool. The reaction mixture is concentrated to dryness andthen taken up in dichloromethane, filtered over Celite and thenconcentrated to dryness again. The residue is then purified bychromatography over silica gel using dichloromethane and ethyl acetateas eluants to provide the expected product in the form of a solid.

¹H NMR: δ (400 MHz; dmso-d6; 300K): 7.55 (s, 1H, pyrazole); 7.23 (s, 1H,pyrazole); 7.18 (broad s, 1H, NH2-Ph); 6.64 (m, 4H, aromatic Hs); 3.77(s, 3H, CH₃-pyrazole); 0.90 (s, 9H, Si (CH₂)₂CH(CH₃)₂); 0.12 (s, 6H, Si(CH₂)₂CH(CH₃)₂)

IR: ν —NH⁺: 3275 cm⁻¹; ν Ar and C═N: 1577 and 1502 cm⁻¹; ν —Si—C—: 1236cm⁻¹; ν —Si—O—: 898 cm⁻¹; ν —Si—C—: 828, 774 cm⁻¹

Preparation 2″: 4-{[tert-Butyl(dimethyl)silyl]oxy}-N-phenylaniline

To a solution of 12 g of 4-anilinophenol (64.7 mmol) in 200 mL ofacetonitrile there are added, at ambient temperature, 6.7 g of imidazole(97.05 mmol) and 11.7 g of tert-butyl(dimethyl)silyl chloride (77.64mmol). The batch is stirred at 70° C. for 4 hours. The reaction mixtureis then poured into water and extracted with ether. The organic phase isthen dried over MgSO₄, then filtered and evaporated to dryness. Thecrude product thereby obtained is then purified by chromatography oversilica gel using petroleum ether and dichloromethane as eluants. Thetitle product is obtained in the form of a powder.

¹H NMR: δ (400 MHz; dmso-d6; 300K): 7.84 (s, 1H NH); 7.17 (t, 2Haniline); 6.98 (d, 2H phenoxy); 6.94 (d, 2H aniline); 6.76 (d, 2Hphenoxy); 6.72 (t, 1H aniline); 0.95 (s, 9H tert-butyl); 0.15 (s, 6Hdimethyl)

IR: ν: >NH: 3403 cm⁻¹; ν: >Ar: 1597 cm⁻¹

Preparation 3″: tert-Butyl5-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-1H-indole-1-carboxylate

The procedure is in accordance with the process of Preparation 1″,replacing the 4-bromo-1-methyl-1H-pyrazole used in Step B by tert-butyl5-bromo-1H-indole-1-carboxylate.

¹H NMR: δ (400 MHz; dmso-d6; 300K): 7.85 (d, 1H); 7.78 (s, 1H); 7.55 (d,1H); 7.15 (d, 1H); 6.95 (m, 3H); 6.75 (d, 2H); 6.58 (d, 1H); 1.65 (s,9H); 1.00 (s, 9H); 0.2 (s, 6H)

Preparation 4″:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indol-5-amine

The procedure is in accordance with the process of Preparation 1″,replacing the 4-bromo-1-methyl-1H-pyrazole used in Step B by5-bromo-1-methyl-1H-indole.

Preparation 5″:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-indazol-5-amine

The procedure is in accordance with the process of Preparation 1″,replacing the 4-bromo-1-methyl-1H-pyrazole used in Step B by5-bromo-1-methyl-1H-indazole.

Preparation 6″:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-3-fluoro-4-methylaniline

The procedure is in accordance with the process of Preparation 1′″,replacing the 4-bromo-1-methyl-1H-pyrazole used in Step B by4-bromo-2-fluoro-1-methylbenzene.

Preparation 7″:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-3-fluoroaniline

The procedure is in accordance with the process of Preparation 1″,replacing the 4-bromo-1-methyl-1H-pyrazole used in Step B by1-bromo-3-fluorobenzene.

Preparation 8″: 4-Benzyloxy-N-phenyl-aniline

To a solution of 4-hydroxy-N-phenyl-aniline (30 g; 162 mmol) inacetonitrile (400 mL) there are added 58 g of Cs₂CO₃ (178 mmol) andstirring is carried out for 15 minutes at ambient temperature. Benzylbromide (22.5 mL; 178 mmol) is then added dropwise and then the reactionmixture is refluxed for 4 hours. After filtering and rinsing withacetonitrile, the filtrate is concentrated and purified bychromatography over silica gel using petroleum ether and ethyl acetateas eluants. The title product is then obtained in the form of acolourless solid.

¹H NMR: δ (400 MHz; dmso-d6; 300K): 7.80 (m, 1H, NH); 7.45 (m, 2H,aryl); 7.40 (m, 2H, aryl); 7.30 (m, 1H, aryl); 7.15 (s, 2H, aryl); 7.05(d, 2H, aryl); 6.9-7.0 (m, 41-1, aryl); 6.70 (t, 1H, aryl); 5.05 (s, 2H,benzyl).

IR: ν: >NH: 3408 cm⁻¹

Preparation 9″:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)pyridin-4-amine

The procedure is in accordance with the process of Preparation 1″,replacing the 4-bromo-1-methyl-1H-pyrazole used in Step B by4-bromopyridine.

IR: ν —NH—: 3200 and 2500 cm⁻¹; ν: —Si—O—: 902 cm⁻¹; ν: —Si—C—: 820 cm⁻¹

Preparation 10″:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-4-fluoroaniline

The procedure is in accordance with the process of Preparation 1″,replacing the 4-bromo-1-methyl-1H-pyrazole used in Step B by1-bromo-4-fluorobenzene.

Preparation 11″:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-amine

The procedure is in accordance with the process of Preparation 1″,replacing the 4-bromo-1-methyl-1H-pyrazole used in Step B by5-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine (obtained in accordance witha protocol from the literature: Heterocycles, 60(4), 865, 2003).

IR: ν: —NH—: 3278 cm⁻¹; ν: aromatic —C═C— moieties: 1605 cm⁻¹

Preparation 12″:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-2-methoxy-pyrimidin-5-amine

The procedure is in accordance with the process of Preparation 1″,replacing the 4-bromo-1-methyl-1H-pyrazole used in Step B by5-bromo-2-methoxypyrimidine.

Preparation 13″:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-amine

The procedure is in accordance with the process of Preparation r,replacing the 4-bromo-1-methyl-1H-pyrazole used in Step B by5-bromo-1-methyl-2,3-dihydro-1H-pyrrolo-[2,3-h]pyridine.

Preparation 14″:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-1H-benzimidazol-5-amine

The procedure is in accordance with the process of Preparation 1″,replacing the 4-bromo-1-methyl-1H-pyrazole used in Step B by5-bromo-1-methyl-1H-benzimidazole.

Preparation 15″:N⁴-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-N²,N²-dimethyl-pyridine-2,4-diamine

The procedure is in accordance with the process of Preparation 1″,replacing the 4-bromo-1-methyl-1H-pyrazole used in Step B by4-bromo-N,N-dimethylpyridin-2-amine.

Preparation 16″:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)pyrazolo[1,5-a]-pyrimidin-6-amine

The procedure is in accordance with the process of Preparation 1″,replacing the 4-bromo-1-methyl-1H-pyrazole used in Step B by6-bromopyrazolo[1,5-a]pyrimidine.

IR: ν —NH—: 3272 cm⁻¹; ν —C═N—: 1634 cm⁻¹; ν 1616 cm⁻¹

Preparation 17″:N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-1-methyl-pyrazolo-[3,4-b]pyridin-5-amine

The procedure is in accordance with the process of Preparation 1″,replacing the 4-bromo-1-methyl-1H-pyrazole used in Step B by5-bromo-1-methyl-pyrazolo[3,4-b]pyridine (obtained in accordance with aprotocol from the literature: WO 2006/052568 starting from2-methyl-pyrazol-3-amine and 2-bromopropanedial).

Preparation 18″:4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)-1,5-dimethyl-1H-pyrrole-2-carbonitrileStep A: 4-Bromo-1,5-dimethyl-1H-pyrrole-2-carbonitrile

A solution of bromine (6.58 mL, 0.13 mol) in acetic acid (60 mL) isadded dropwise, with the aid of a dropping funnel, to a solution of1,5-dimethyl-1H-pyrrole-2-carbonitrile (15.0 g, 0.12 mol) in acetic acid(300 mL). The batch is stirred at ambient temperature for 24 hours. Thereaction mixture is then poured into a beaker containing 300 mL ofwater. The solid formed is filtered off and rinsed with water. It isthen dissolved in dichloromethane (300 mL) and the organic phase iswashed with brine, dried over Na₂SO₄, filtered and concentrated in vacuoto yield the expected product in the form of a solid.

¹H NMR (CDCl₃) δ ppm: 2.25 (s, 3H), 3.67 (s, 3H), 6.74 (s, 1 II)

Step B:4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)-1,5-dimethyl-1H-pyrrole-2-carbonitrile

A solution of the compound of the above Step (1.5 g, 7.53 mmol),4-[(tert-butyldimethylsilyl)oxy]aniline (2.02 g, 9.04 mmol), sodiumtert-butylate (1.45 g, 15.06 mmol) and2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.13 g, 0.30mmol) in toluene (20 mL) is purged with nitrogen.Tris(dibenzylideneacetone)-dipalladium(0) (0.28 g, 0.30 mmol) is added,and then the reaction mixture is heated at 90° C. until the reaction iscomplete (monitored by TLC). Heating is stopped and the mixture isallowed to return to ambient temperature. Water (75 mL) is added and themixture is extracted with ethyl acetate (3×75 mL). The combined organicphases are washed with brine and then concentrated. The crude product isabsorbed onto silica gel and purified by chromatography over silica gelusing ethyl acetate and heptane as eluants. The product thereby obtainedis dissolved in heptane in the warm state and is allowed to precipitate,with stirring, at ambient temperature, and then at 0° C. The solid isfiltered off and the operation is repeated on the filtrate to yield theexpected compound in the form of a solid.

¹H NMR (400 MHz, CDCl₃) δ ppm: 0.15 (s, 6H), 0.97 (s, 9H), 2.13 (s, 3H),3.66 (s, 3H), 4.68 (br. s, 1H), 6.49 (d, J=8.5 Hz, 2H), 6.64 (s, 1H),6.66 (d, J=8.7 Hz, 2H)

¹³C NMR (100 MHz, CDCl₃) δ ppm: 4.34, 9.72, 18.30, 25.88, 32.94, 101.27,114.37, 114.70, 116.41, 120.73, 124.52, 131.23, 141.54, 148.27

MS (ESI+): [M+H]⁺ measured: 342.3

Preparation 19″:4-[(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)amino]-1-methyl-1H-pyrrole-2-carbonitrileStep A: 1-Methyl-1H-pyrrole-2-carbonitrile

N,N-Dimethylformamide (3 mL) and 1,4-diazabicyclo[2.2.2]octane (0.49 g,4.3 mmol) are added to a solution of pyrrole-2-carbonitrile (4 g, 43.4mmol) in dimethyl carbonate (56 mL). The solution is stirred at 90° C.for 15 hours, and is then heated at 110° C. for 8 hours. The mixture iscooled to ambient temperature, and then ethyl acetate (80 mL) is added.The phases are separated and the organic phase is washed with water(2×80 mL) and 1N aqueous HCl solution (1×80 mL). The combined aqueousphases are extracted again with ethyl acetate (1×80 mL). The combinedorganic phases are washed with brine (1×80 mL), dried over MgSO₄,filtered and concentrated in vacuo to obtain the expected product in theform of a liquid.

¹H NMR (400 MHz, CDCl₃) δ ppm: 3.78 (m, 2H), 6.12-6.18 (m, 1H),6.74-6.82 (m, 1H)

Step B: 4-Bromo-1-methyl-1H-pyrrole-2-carbonitrile

N-Bromosuccinimide (6.2 g, 34.9 mmol) is added to a solution of1-methyl-1H-pyrrole-2-carbonitrile (3.7 g, 34.9 mmol) inN,N-dimethylformamide (150 mL). The solution is stirred for 15 hours atambient temperature. Another amount of N-bromosuccinimide (2.0 g, 11mmol) is added and the mixture is stirred for 3 hours. Silica (7 g) isthen added and the suspension is then evaporated to dryness. Thematerial pre-absorbed onto the silica is placed on a silica gel columnand the product is purified by chromatography over silica gel usingethyl acetate and heptane as eluants to obtain the expected product inthe form of a solid.

¹H NMR (400 MHz, CDCl₃) δ ppm: 3.77 (s, 3H), 6.75 (d, J=1.7 Hz, 1H),6.80 (d, J=1.7 Hz, 1H)

Step C:4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)-1-methyl-1H-pyrrole-2-carbonitrile

Nitrogen is bubbled through a solution of4-bromo-1-methyl-1H-pyrrole-2-carbonitrile (2.82 g, 15.2 mmol) and4-[(tert-butyldimethylsilyl)oxy]aniline (4.08 g, 18.3 mmol) in toluene(55 mL) for 5 minutes. Sodium tert-butylate (2.92 g, 30.4 mmol),tris(dibenzylideneacetone)dipalladium(0) (556 mg, 0.6 mmol) and2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (255 mg, 0.6mmol) are then added to the reaction mixture. The mixture is stirred for1 hour at 80° C. under nitrogen. The suspension is then cooled toambient temperature and filtered over Celite. The Celite cake is thenrinsed with ethyl acetate. The filtrate is washed with water and thenwith brine. The organic phase is dried over MgSO₄, filtered andconcentrated in vacuo. The product is purified twice by chromatographyover silica gel using ethyl acetate and heptane as eluants, and then bytrituration in heptane to obtain the expected product in the form of asolid.

¹H NMR (400 MHz, CDCl₃) δ ppm: 0.16 (s, 6H), 0.97 (s, 9H), 3.73 (s, 3H),6.57 (d, J=1.9 Hz, 1H), 6.64-6.66 (m, 1H), 6.70 (s, 4H); NMR

¹³C NMR (100 MHz, CDCl₃) δ ppm: −4.48, 18.17, 25.72, 35.46, 103.01,113.56, 113.69, 115.92, 119.55, 120.67, 129.04, 139.94, 148.85

MS (ESI+): [M+H]⁺ 328.25

Preparation 20″:N-[4-[tert-Butyl(dimethyl)silyl]oxy-3-fluoro-phenyl]-1-methyl-1H-pyrazol-4-amine

The procedure is in accordance with the protocol of Preparation 1″,replacing the 4-aminophenol used in Step A by 2-fluoro-4-aminophenol.

¹H NMR (400 MHz, dmso-d6) δ ppm: 7.59 (bs, 1H), 7.39 (m, 1H), 7.24 (d,1H), 6.74 (dd, 1H), 6.52 (dd, 1H), 6.42 (ddd, 1H), 3.76 (s, 3H), 0.92(s, 9H), 0.1 (d, 6H)

Preparation 21″:2-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)pyridine-4-carbonitrile

A solution composed of 2-bromo-4-pyridinecarbonitrile (5.00 g, 36.1mmol), 4-[(tert-butyldimethylsilyl)oxy]aniline (8.06 g, 36.1 mmol),sodium tert-butylate (4.50 g, 46.9 mmol) and2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.458 g, 1.08mmol) in toluene (50 mL) is purged with nitrogen.Tris(dibenzylideneacetone)-dipalladium(0) (0.99 g, 1.08 mmol) is thenadded to the reaction mixture, and then the batch is heated at 50° C.for 1.5 hours. The mixture is then allowed to cool to ambienttemperature. Water is added and the reaction mixture is extracted withethyl acetate (3×20 mL). The combined organic phases are washed withbrine, and then concentrated under reduced pressure. The crude productis absorbed onto silica gel and purified by chromatography over silicagel using ethyl acetate and heptane as eluants. The product obtained isdissolved in the warm state in heptane and precipitates, with stirring,at ambient temperature, and then at 0° C. After filtration, the expectedcompound is obtained in the form of a solid.

¹H NMR (400 MHz, CDCl₃) δ ppm: 0.22 (s, 6H), 1.00 (s, 9H), 6.61 (br. s,1H), 6.81-6.84 (m, 2H), 6.84-6.89 (m, 2H), 7.12-7.17 (m, 2H), 8.26 (dd,J=5.1, 0.9 Hz, 1H)

¹³C NMR (100 MHz, CDCl₃) δ ppm: −4.29, 18.31, 25.78, 109.11, 114.73,117.23, 121.17, 121.74, 124.93, 132.12, 149.79, 153.45, 158.00

MS (ESI+): [M+H]⁺ 326.19

Preparation 22″:N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-1-tetrahydrofuran-3-yl-pyrazol-4-amine

4-[tert-Butyl(dimethyl)silyl]oxyaniline (0.92 g, 3.48 mmol) and4-iodo-1-tetrahydrofuran-3-yl-pyrazole (0.78 g, 3.48 mmol) dissolved inanhydrous tetrahydrofuran (20 mL) are stirred for one hour at ambienttemperature in the presence of sodium tert-butylate (1.7 mL, 2M solutionin THF) andchloro(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)(84 mg, 0.122 mmol). The reaction mixture is filtered over Celite andthen evaporated to dryness. The residue is crystallised from a mixtureof heptane/ethyl acetate, filtered and washed with heptane and thenpurified by chromatography over silica gel using dichloromethane andmethanol as eluants to yield the expected product.

¹H NMR (500 MHz, dmso-d6, 300 K) δ ppm: 7.62 (d, 1H, pyrazole-1-15),7.29 (d, 1H, pyrazole-H3), 7.26 (s, 1H, NH), 6.68 (d, 2H, Ar—H), 6.64(d, 2H, Ar—H), 4.93 (m, 1H, THF-3′H), 3.95 (m, 1H, THF-5′H), 3.94 (m,1H, THF-2′H), 3.87 (m, 1H, THF-2′H), 3.80 (m, 1H, THF-5′H), 2.33 (m, 1H,THF-4′H), 2.27 (m, 1H, THF-4′H), 0.93 (s, 9H, ^(t)Bu), 0.12 (s, 6H, Me)

IR: ν C—H: 2857 cm⁻¹; ν aromatic: 1505 cm⁻¹; ν Si—C: 1249 cm⁻¹

Preparation 23″:6-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)pyridine-2-carbonitrile

4-Aminophenol (3.3 g, 30.2 mmol) is added to a solution of6-chloropyridine-2-carbonitrile (3.5 g, 25.3 mmol) in1-methyl-2-pyrrolidinone (70 mL). The reaction mixture is heated at140-150° C. for 16 hours in a sealed flask. The batch is then cooled toambient temperature. Imidazole (3.4 g, 49.9 mmol) andtert-butyl(dimethyl)silyl chloride (7.6 g, 50.4 mmol) are subsequentlyadded and the mixture is stirred for 16 hours at ambient temperature.The mixture is diluted with water (140 mL) and the product is extractedwith AcOEt (4×50 mL). The organic phases are combined and washed withwater (3×50 mL), and then brine (1×50 mL). The organic phase is thendried over MgSO₄, filtered and concentrated in vacuo. The crude productis purified by chromatography over silica gel using ethyl acetate andheptane as eluants to obtain the title product.

¹H NMR (400 MHz, CDCl₃) δ ppm: 0.20 (s, 6H), 0.99 (s, 9H), 6.74 (dd,J=7.6, 4.9 Hz, 1H), 6.81-6.88 (m, 3H), 7.36-7.42 (m, 2H), 7.74 (dd,J=7.6, 1.9 Hz., 1H), 8.34 (dd, J=4.9, 1.9 Hz, 1H)

¹³C NMR (100 MHz, CDCl₃) δ ppm: −4.38, 18.21, 25.73, 92.58, 113.50,116.53, 120.30, 123.20, 131.97, 141.67, 152.42, 152.45, 156.51

MS (ESI): [M+H]⁺ 326.24

Preparation 24″:4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)pyrimidine-2-carbonitrileStep A:N-{4-[(tert-Butyldimethylsilyl)oxy]phenyl}-2-chloropyrimidin-4-amine

4-Aminophenol (8.8 g, 80.6 mmol) and triethylamine (18.6 mL, 133.4 mmol)are added to a solution of 2,4-dichloropyrimidine (10.0 g, 67.1 mmol) inethanol (150 mL). The reaction mixture is heated at 150° C. for 14 hoursin a sealed flask. The batch is then cooled to ambient temperature andthe solvent is evaporated off in vacuo. Dichloromethane (200 mL) isadded to the residue, and then imidazole (9.1 g, 133.7 mmol) andtert-butyl(dimethyl)silyl chloride (12.1 g, 80.3 mmol) are added. Themixture is stirred for 15 hours at ambient temperature. The reactionmixture is diluted with water (200 mL). The phases are separated and theorganic phase is washed with brine (1×100 mL). It is then dried overMgSO₄, filtered and concentrated in vacuo. The residue is purified bychromatography over silica gel using ethyl acetate and heptane aseluants to obtain a solid. The latter is triturated in heptane, filteredoff and rinsed with heptane to yield the expected compound in the formof a solid.

¹H NMR (400 MHz, dmso-d6) δ ppm: 0.22 (s, 6H), 0.99 (s, 9H), 6.42 (d,J=5.9 Hz, 1H), 6.81 (br. s, 1H), 6.85-6.90 (m, 1H), 7.13 (d, J=8.7 Hz,2H), 8.07 (d, J=5.9 Hz, 2H)

Step B:4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)pyrimidine-2-carbonitrile

Anhydrous N,N-dimethylformamide (10 mL) is placed under nitrogen in aflask and then the compound of Step A (670 mg, 2.0 mmol) is added. Zinccyanide (468 mg, 4.0 mmol) and tetrakis(triphenylphosphine)palladium(0)(404 mg, 0.3 mmol) are subsequently added. Nitrogen is bubbled throughthe solution for 5 minutes and then the reaction mixture is stirred at120° C. for 2 hours under a nitrogen atmosphere. The reaction, monitoredby LC-MS, is complete. The mixture is cooled to ambient temperature, andthen water (15 mL) is added thereto. The product is extracted with AcOEt(3×25 mL). The organic phases are combined and washed with water (4×25mL), and then with brine (1×25 mL). The organic phase is dried overMgSO₄, filtered and concentrated in vacuo. The residue is purified bychromatography over silica gel using ethyl acetate and heptane aseluants to obtain the expected compound in the form of a solid.

¹H NMR (400 MHz, CDCl₃) δ ppm: 0.22 (s, 6H), 0.99 (s, 9H), 6.63 (d,J=6.1 Hz, 1H), 6.86-6.92 (m, 2H), 7.03 (br. s, 1H), 7.17 (d, J=8.5 Hz,2H), 8.22 (d, J=6.1 Hz, 1H)

¹³C NMR (100 MHz, CDCl₃) δ ppm: −4.51, 18.10, 25.55, 106.32, 115.92,121.00, 125.22, 129.73, 144.55, 154.16, 156.07, 161.56

Preparation 25″:N-{4-[(tert-Butyldimethylsilyl)oxy]phenyl}-1-trideuteriomethyl-1H-pyrazol-4-amineStep A: 4-Bromo-1-trideuteriomethyl-1H-pyrazole

4-Bromo-1H-pyrazole (9.05 g, 61.6 mmol) is added in portions to asuspension of NaH (60% in oil) (2.83 g, 70.8 mmol) in tetrahydrofuran(90 mL) cooled in an ice bath. After having taken away the ice bath, thesolution is stirred at ambient temperature for 0.5 hours. It is againcooled in an ice bath and iodomethane-d₃ (5.0 mL, 80.3 mmol) is added.The solution is stirred at ambient temperature for 19 hours. Thesuspension is then concentrated. The evaporation residue is trituratedwith MTBE (90 mL) and filtered. The filtrate is concentrated in vacuo toobtain the expected compound in the form of an oil.

¹H NMR (400 MHz, CDCl₃) δ ppm: 7.37 (s, 1H), 7.43 (s, 1H)

Step B:N-{4-[(tert-Butyldimethylsilyl)oxy]phenyl}-1-trideuteriomethyl-1H-pyrazol-4-amine

4-Bromo-1-trideuteriomethyl-1H-pyrazole (9.6 g, 58.5 mmol),4-[(tert-butyldimethyl-silyl)oxy]aniline (14.4 g, 64.6 mmol) and toluene(150 mL) are added to a 500-ml three-necked flask. The solution isdegassed with nitrogen for 15 minutes, and then sodium ten-butylate(11.4 g, 0.12 mol),2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.77 g, 1.81mmol) and tris(dibenzylideneacetone)dipalladium(0) (1.64 g, 1.79 mmol)are successively added. The suspension is heated at 85° C. for 1.5hours. The reaction mixture is then cooled to ambient temperature andwater (270 mL) is added. The mixture is stirred for 30 minutes. Celite(30 g) is then added and the suspension is filtered on a bed of Celite.

The phases of the filtrate are separated and the aqueous phase isextracted with ethyl acetate (3×200 mL). The combined organic phases aredried over Na₂SO₄ and filtered. Silica (36 g) is added to the filtrateand the batch is evaporated to dryness. The product is purified bychromatography over silica gel using ethyl acetate and heptane aseluants. The product obtained is recrystallised from heptane (80 mL) toobtain the expected compound.

¹H NMR (400 MHz, CDCl₃) δ ppm: 0.16 (s, 6H), 0.97 (s, 9H), 4.92 (s, 1H),6.61-6.73 (m, 4H), 7.25 (s, 1H), 7.36 (s, 1H)

¹³C NMR (100 MHz, CDCl₃) δ ppm: −4.37, 18.28, 25.86, 38.67 (sept.,¹J_(C-D)=21.0 Hz), 115.12, 120.73, 123.76, 126.52, 134.74, 141.07,148.43

MS (ESI): [M+H]⁺ 307.08

Preparation 26″:N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-1-(oxetan-3-yl)-1H-pyrazol-4-amineStep A: 4-Bromo-1-(oxetan-3-yl)-1H-pyrazole

4-Bromo-1H-pyrazole (1.53 g. 10.7 mmol) is dissolved in anhydrousdimethylformamide (15 mL). 3-Bromooxetane (2.0 g, 14.6 mmol) and caesiumcarbonate (4.7 g, 14 mmol) are successively added thereto. The reactionmixture is heated for 8 hours at 130° C. in a sealed flask. At the endof the reaction, the solvent is evaporated off in vacuo and the residueis purified by chromatography over silica gel using dichloromethanecontaining diethylamine and methanol as eluants to yield the expectedcompound.

Step B:N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-1-(oxetan-3-yl)-1H-pyrazol-4-amine

4-[tert-Butyl(dimethyl)silyl]oxyaniline (1.5 g, 7.2 mmol) and4-bromo-1-(oxetan-3-yl)-pyrazole (1.6 g, 7.2 mmol) dissolved inanhydrous tetrahydrofuran (25 mL) are stirred for 3 hours at ambienttemperature in the presence of sodium tert-butylate (3.7 mL, 2M solutionin THF) and chloro(2-di-tert-butyl phosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (101 mg,0.145 mmol). The reaction mixture is filtered over Celite and thenevaporated to dryness. The residue is purified by chromatography oversilica gel using dichloromethane containing diethylamine and ethylacetate as eluants to yield the expected product.

¹H NMR (500 MHz, dmso-d6, 300 K) δ ppm: 7.76 (s, 1H, pyrazole-5′H), 7.40(s, 1H, pyrazole-3′H), 7.34 (br s, 11-1, NH), 6.70 (d, 2H, Ar—H), 6.65(d, 2H, Ar—H), 5.49 (m, 1H, oxetane), 4.89 (d, 4H, oxetane), 0.93 (s,9H, Su), 0.13 (s, 6H, Me)

IR: ν: C—H: 2955 cm⁻¹; aromatic: 1505 cm⁻¹: Si—C: 1237 cm⁻¹

Preparation 27″: Mixture ofN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1,5-dimethyl-1H-pyrazol-4-amineandN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1,3-dimethyl-1H-pyrazol-4-amineStep A: Mixture of 4-bromo-1,5-dimethyl-1H-pyrazole and4-bromo-1,3-dimethyl-1H-pyrazole

To a suspension of NaH 60% in oil (0.3 g; 7.45 mmol) in tetrahydrofuran(150 mL) there is added, at 10° C., 4-bromo-3-methyl-1H-pyrazoledissolved in 15 mL of tetrahydrofuran dropwise, over 15 minutes. Afterstirring for 40 minutes at ambient temperature, iodomethane (0.45 mL;7.45 mmol) is added dropwise, and then the reaction mixture is stirredovernight. After adding water, the reaction mixture is evaporated andtaken up in dichloromethane. The organic phase is separated off anddried over MgSO₄, filtered and concentrated to dryness. The residue ispurified by chromatography over silica gel to yield a mixture of thetitle compounds (4-bromo-1,3-dimethyl-pyrazole and4-bromo-1,5-dimethyl-pyrazole respectively in a ratio of 4:6).

4-bromo-1,5-dimethyl-1H-pyrazole

¹H NMR (500 MHz, dmso-d6) δ ppm: 7.41 (s, 1H), 3.76 (s, 3H), 2.22 (s,3H)

4-bromo-1,3-dimethyl-1H-pyrazole

¹H NMR (500 MHz, dmso-d6) δ ppm: 7.81 (s, 1H), 3.74 (s, 3H), 2.09 (s,3H)

Step B: Mixture ofN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1,5-dimethyl-1H-pyrazol-4-amineandN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1,3-dimethyl-1H-pyrazol-4-amine

The procedure is in accordance with Step B of Preparation 1″, replacingthe 4-bromo-1-methyl-1H-pyrazole by the mixture of isomers from Step A.A mixture of isomers in a ratio of 4:6 is obtained (respectivelyN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1,5-dimethyl-1H-pyrazol-4-amineandN-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1,3-dimethyl-1H-pyrazol-4-amine).

Preparation 28″:N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-1-cyclopropyl-1H-pyrazol-4-amineStep A: 4-Bromo-1-cyclopropyl-1H-pyrazole

4-Bromo-1H-pyrazole (1.76 g, 12 mmol) is dissolved in anhydrousdimethylformamide (15 mL). Cyclopropyl bromide (2.9 mL, 36 mmol) andcaesium carbonate (7.8 g, 24 mmol) are successively added thereto. Thereaction mixture is heated for 15 hours at 160° C. in a sealed flask. Atthe end of the reaction, the solvent is evaporated off in vacuo and theresidue is purified by chromatography over silica gel using heptane anddichloromethane as eluants to yield the expected compound.

Step B:N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-1-cyclopropyl-1H-pyrazol-4-amine

4-[tert-Butyl(dimethyl)silyl]oxyaniline (1.64 g, 7.3 mmol) and4-bromo-1-cyclopropyl-1H-pyrazole (1.4 g, 7.3 mmol) dissolved inanhydrous tetrahydrofuran (30 mL) are stirred for 3 hours at ambienttemperature in the presence of sodium tert-butylate (3.7 mL, 2M solutionin THF) andchloro(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)(101 mg, 0.146 mmol). The reaction mixture is filtered over Celite andthen evaporated to dryness. The residue is purified by chromatographyover silica gel using heptane and ethyl acetate as eluants to yield theexpected product.

¹H NMR (500 MHz, dmso-d6, 300 K) δ ppm: 7.61 (s, 1H, pyrazole-5′H), 7.23(s, 1H, pyrazole-3′H), 7.22 (br s, 1H, NH), 6.65 (d, 2H, Ar—H), 6.63 (d,2H, Ar—H), 3.64 (in, 1H, cyclopropyl-H), 1.00-0.91 (m, 4H, cyclopropyl),0.93 (s, 9H, Su), 0.12 (s, 6H, Me)

IR: ν: C—H: 2930 cm⁻¹; aromatic: 1504 cm⁻¹: Si—C: 1237 cm⁻¹

High-resolution mass spectrometry (ESI+):

Empirical formula: C₁₈H₂₇N₃OSi

[M+H]⁺ calculated: 330.2003

[M+H]⁺ measured: 330.1989

Preparation 29″: 1,5-Dimethyl-4-(phenylamino)-1H-pyrrole-2-carbonitrile

The procedure is in accordance with the protocol of Preparation 1″,replacing the 4-{[tert-butyl(dimethyl)silyl]oxy}aniline used in Step Bby aniline.

¹H NMR (400 MHz, dmso-d6) δ ppm: 7.19 (s, 1H), 7.05 (t, 2H), 6.79 (s,1H), 6.6 (m, 3H), 3.61 (s, 3H), 2.1 (s, 3H)

Preparation 30″: 1-Methyl-N-phenyl-1H-pyrrolo[2,3-b]pyridin-6-amine

The procedure is in accordance with the protocol of Step B ofPreparation 1″ using aniline and5-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine (obtained in accordance witha protocol from the literature: Heterocycles, 60(4), 865, 2003).

¹H NMR (400 MHz, dmso-d6) δ ppm: 8.1 (d, 1H), 7.9 (s, 1H), 7.7 (d, 1H),7.45 (d, 1H), 7.17 (t, 2H), 6.9 (d, 2H), 6.7 (1, 1H), 6.38 (d, 1 II),3.8 (s, 3H)

Preparation 31″:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-1-trideuteriomethyl-1H-pyrrolo[2,3-b]pyridin-5-amine

The procedure is in accordance with the process of Preparation 1″,replacing the 4-bromo-1-methyl-1H-pyrazole used in Step B by5-bromo-1-(trideuteriomethyl)-1H-pyrrolo[2,3-b]pyridine (obtained inaccordance with a protocol from the literature Heterocycles, 60(4), 865,2003, replacing the methyl iodide by trideuterated methyl iodide).

¹H NMR (400 MHz, dmso-d6) δ ppm: 8.05 (d, 1H), 7.6 (m+d, 2H), 7.4 (d,1H), 6.85/6.7 (2d, 4H), 6.3 (d, 1H), 0.95 (s, 9H), 0.15 (s, 6H)

Preparation 32″:4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)-1-trideuteriomethyl-1H-pyrrole-2-carbonitrileStep A: 1-Trideuteriomethyl-1H-pyrrole-2-carbonitrile

NaH (60% in oil) (2.61 g, 65.2 mmol) is suspended in tetrahydrofuran(110 mL) at 0° C. 1H-Pyrrole-2-carbonitrile (5 g, 54.3 mmol) is addeddropwise over 10 minutes. The reaction mixture is then warmed up toambient temperature over 30 minutes. It is again cooled to 0° C., andthen iodomethane-d₃ (10.23 g, 70.6 mmol) is added. The reaction mixtureis stirred for 16 hours under nitrogen at ambient temperature. Thereaction mixture is then evaporated under reduced pressure, and thenethyl acetate (200 mL) and water (200 mL) are added. The phases areseparated, and the aqueous phase is extracted with ethyl acetate (2×200mL). The combined organic phases are washed with brine (1×80 mL), driedover MgSO₄, filtered and concentrated in vacuo. The residue is purifiedby chromatography over silica gel using ethyl acetate and heptane aseluants. The fractions are combined and evaporated in vacuo to obtainthe expected compound.

¹H NMR (400 MHz, CDCl₃) δ ppm: 6.13 (dd, J=2.7, 3.9 Hz, 1H), 6.75 (dd,J=1.5, 4.1 Hz, 1H), 6.79 (dd, J=1.7, 2.6 Hz, 1H)

Step B: 4-Bromo-1-trideuteriomethyl-1H-pyrrole-2-carbonitrile

N-Bromosuccinimide (6.68 g, 37.5 mmol) is added to a solution of thecompound of the above Step (4.09 g, 37.5 mmol) in N,N-dimethylformamide(188 mL). The solution is stirred for 16 hours at ambient temperature.The residue is purified by chromatography using ethyl acetate andheptane as eluants to obtain the expected compound in the form of asolid.

¹H NMR (400 MHz, CDCl₃) δ ppm: 6.75 (d, J=1.7 Hz, 1H), 6.80 (d, J=1.7Hz, 1H)

Step C:4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)-1-trideuteriomethyl-1H-pyrrole-2-carbonitrile

Nitrogen is bubbled through a solution composed of the compound obtainedin the above Step (5.85 g, 31.1 mmol),4-[(tert-butyldimethylsilyl)oxy]aniline (8 g, 35.8 mmol), sodiumtert-butylate (3.88 g, 40.4 mmol) and2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (662 mg, 1.56mmol) in toluene (260 mL) for 5 minutes.Tris(dibenzylideneacetone)-dipalladium(0) (1.43 g, 1.56 mmol) is thenadded. The mixture is stirred for 1 hour at 70° C. under nitrogen. Thesuspension is then cooled to ambient temperature, diluted with ethylacetate and filtered over Celite. The Celite cake is then rinsed withethyl acetate. The filtrate is washed with water (3 times), and thenbrine (once). The organic phase is dried over Na₂SO₄, filtered andconcentrated in vacuo. The product is purified twice by chromatographyover silica gel using ethyl acetate and heptane as eluants, and then byreverse-phase chromatography using methanol and water as eluants toobtain the expected compound in the form of a powder.

¹H NMR (400 MHz, CDCl₃) δ ppm: 0.17 (s, 6H), 0.98 (s, 9H), 4.96 (br. s,1H), 6.57 (d, J=1.9 Hz, 1H), 6.64 (d, J=1.8 Hz, 1H), 6.70 (br. s, 4H)

¹³C NMR (100 MHz, CDCl₃) δ ppm: −4.38, 18.26, 25.83, 34.83, 102.96,113.69, 113.71, 115.95, 119.58, 120.75, 129.14, 140.10, 148.84

MS (ESI): [M+H]⁺ 331.09

Preparation 33″:4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)-1-trideuteriomethyl-5-methyl-1H-pyrrole-2-carbonitrileStep A: 5-Methyl-1H-pyrrole-2-carbonitrile

The compound is prepared in accordance with the protocol described inHeterocycles 2011, 82, 1503.

Step B: 1-Trideuteriomethyl-5-methyl-1H-pyrrole-2-carbonitrile

A solution of 5-methyl-1H-pyrrole-2-carbonitrile (0.30 g, 2.82 mmol) inN,N-dimethyl-formamide (5 mL) is cooled to 0° C. NaH (60% in oil) (0.118g, 2.96 mmol) is added in portions, and the reaction mixture is stirredat 0° C. for 30 minutes. Iodomethane-d₃ (4.15 mL, 67.2 mmol) is added ina single portion, and the reaction mixture is stirred at ambienttemperature until the reaction is complete. It is then diluted withwater (30 mL) and ethyl acetate (15 mL). The phases are separated andthe aqueous phase is extracted a second time with ethyl acetate (15 mL).The combined organic phases are washed with water (1×50 mL), and thenbrine, and dried over Na₂SO₄. After filtration and concentration underreduced pressure, the residue is purified by chromatography over silicagel using ethyl acetate and heptane as eluants to yield the expectedcompound in the form of a solid.

¹H NMR (400 MHz, CDCl₃) δ ppm: 2.25 (s, 3H), 5.91 (dd, J=3.9, 0.6 Hz,1H), 6.69 (d, J=3.9 Hz, 1H)

Step C: 4-Bromo-1-trideuteriomethyl-5-methyl-1H-pyrrole-2-carbonitrile

A solution of bromine (0.133 mL, 2.60 mmol) in acetic acid (1.5 mL) isadded dropwise to a solution of the compound obtained in the above Step(0.305 g, 2.48 mmol) in acetic acid (5.5 mL) previously cooled to 0° C.The reaction mixture is stirred and gradually warmed up to ambienttemperature over a period of 20 hours. The reaction mixture is pouredinto water (50 mL) and the mixture is extracted with dichloromethane(2×50 mL). The organic phase is dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield the expected compound inthe form of a solid.

¹H NMR (400 MHz, CDCl₃) δ ppm: 2.24 (s, 3H), 6.73 (s, 1H)

Step D:4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)-1-trideuteriomethyl-5-methyl-1H-pyrrole-2-carbonitrile

A solution composed of the compound obtained in the above Step (7.00 g,34.6 mmol), 4-[(tert-butyldimethylsilyl)oxy]aniline (8.90 g, 39.8 mmol),sodium tert-butylate (4.33 g, 45.0 mmol) and2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.441 g, 1.04mmol) in toluene (70 mL) is purged with nitrogen.Tris(dibenzylideneacetone)-dipalladium(0) (0.951 g, 1.04 mmol) is added,and then the reaction mixture is heated at 65° C. until the reaction,monitored by TLC, is complete. Heating is stopped and the mixture iscooled to ambient temperature. Water (200 mL) is added and the mixtureis extracted with ethyl acetate (3 times). The combined organic phasesare washed with brine, and then concentrated. The crude product ispurified by chromatography over silica gel using ethyl acetate andheptane as eluants. The product obtained is dissolved in heptane in thewarm state; it is allowed to precipitate out at ambient temperature andthen at 0° C. to yield the expected product in the form of crystals.

¹H NMR (400 MHz, CDCl₃) δ ppm: 0.15 (s, 6H), 0.96 (s, 9H), 2.12 (s, 3H),4.66 (br. s, 1H), 6.46-6.51 (m, 2H), 6.64 (s, 1H), 6.64-6.69 (m, 2H)

¹³C NMR (100 MHz, CDCl₃) δ ppm: −4.37, 9.64, 18.26, 25.84, 31.62-32.87(m), 101.14, 114.35, 114.66, 116.33, 120.68, 124.51, 131.17, 141.53,148.18

MS (ESI): [M+H]⁺ 345.13

Preparation 34″:5-[(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)amino]-1-methyl-1H-pyrazole-3-carbonitrileStep A: 5-Amino-1-methyl-1H-pyrazole-3-carbonitrile

To a suspension of 1-methyl-5-nitro-1H-pyrazole-3-carbonitrile (2 g;13.1 mmol) in a mixture of water (14 mL) and ethanol (120 mL) there areadded HCl 37% (170 μL) and iron filings (5.1 g; 91 mmol). The reactionmixture is heated for 5 hours at 50° C. After cooling to ambienttemperature, the reaction mixture is filtered. The filtrate isconcentrated to dryness and then purified by chromatography over silicagel using dichloromethane and ethyl acetate as eluants to yield theexpected compound in the form of a solid.

¹H NMR (400 MHz, dmso-d6) δ ppm: 5.8 (s, 1H), 5.7 (m, 2H), 3.6 (s, 3H)

Step B:5-[(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)amino]-1-methyl-1H-pyrazole-3-carbonitrile

The procedure is in accordance with the protocol of Step B ofPreparation 1″, replacing the 4-bromo-1-methyl-1H-pyrazole by(4-bromophenoxy)-(tert-butyl)dimethyl-silane and the4-{[tert-butyl(dimethyl)silyl]oxy}aniline by the compound from Step A.

¹H NMR (400 MHz, dmso-d6) δ ppm: 8.15 (s, 1H), 6.9 (d, 2H), 6.75 (d,2H), 6.45 (s, 1H), 3.75 (s, 3H), 0.95 (s, 9H), 0.15 (s, 6H)

Preparation 35″:4-[(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)amino]-5-methyl-1-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-2-carbonitrile

The procedure is in accordance with the process of Preparation 33″,replacing the iodomethane-d₃ in Step B by 2-(chloroethyl)morpholinehydrochloride.

¹H NMR (400 MHz, dmso-d6) δ ppm: 6.85 (s, 1H), 6.75 (s, 1H), 6.6 (d,2H), 6.5 (d, 2H), 4.1 (t, 2H), 3.55 (t, 4H), 2.6 (t, 2H), 2.4 (t, 4H),2.1 (s, 3H), 0.9 (s, 9H), 0.1 (s, 6H)

Preparation 36″:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-2-[2-(morpholin-4-yl)ethoxy]pyrimidin-5-amineStep A: 4-[2-(5-Bromopyrimidin-2-yl)oxyethyl]morpholine

NaH (1.0 g, 25.0 mmol, 60% in oil) suspended in anhydroustetrahydrofuran is cooled at 0° C. in an ice bath under argon, and then2-morpholinoethanol (2.7 g, 20.7 mmol) is added dropwise. The ice bathis withdrawn and the suspension is stirred for 1 hour at ambienttemperature. 5-Bromo-2-chloro-pyrimidine (4.0 g, 20.7 mmol) is thenadded at ambient temperature and the reaction mixture is stirred for 16hours at ambient temperature. Saturated aqueous ammonium chloridesolution (10 mL) and water (10 mL) are added to the reaction mixture;the pH is adjusted to 9 by adding saturated aqueous NaHCO₃ solution. Theresulting solution is extracted 3 times with ethyl acetate, the organicphase is then washed with brine, dried over MgSO₄, and then evaporatedto dryness. The expected compound precipitates out by means of theaddition of petroleum ether.

¹H NMR (400 MHz, dmso-d6) δ ppm: 8.75 (s, 2H), 4.4 (t, 2H), 3.55 (t,4H), 2.7 (t, 2H), 2.45 (t, 4H)

IR (ATR) cm⁻¹: 1562 ν>C═C< and C═N, 787 ν —C—H Ar

Step B:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-2-[2-(morpholin-4-yl)ethoxy]-pyrimidin-5-amine

The procedure is in accordance with the protocol of Step B ofPreparation 1″, replacing the 4-bromo-1-methyl-1H-pyrazole by thecompound from Step A.

¹H NMR (400 MHz, dmso-d6) δ ppm: 8.3 (s, 2H), 7.8 (s, 1H), 6.9/6.75 (2d,4H), 4.35 (t, 2H), 3.55 (t, 4H), 2.7 (t, 2H), 2.45 (t, 4H), 0.95 (s,9H), 0.15 (s, 6H)

IR (ATR) cm⁻¹: 3300 ν —NH, 1506 ν —NH, 837 ν —Si-Me, 837 and 778 ν —CHAr

Preparation 37″:4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)-1,3-dimethyl-1H-pyrrole-2-carbonitrileStep A: 4-Methyl-N-(prop-2-en-1-yl)benzene-1-sulphonamide

Allylamine (10.6 mL, 0.14 mol) is added over a period of 4 minutes to asolution of tosyl chloride (25.1 g, 0.13 mol) in dichloromethane (250mL) cooled in an ice bath. Triethylamine (24 mL, 0.18 mol) is added andthen the solution is stirred at ambient to temperature for 1.25 hours.Aqueous 3N HCl solution (60 mL) is added and the phases are thenseparated. The organic phase is washed with another amount of aqueous 3NHCl solution (60 mL) and then with 5% aqueous sodium bicarbonatesolution (60 mL). The organic phase is dried over Na₂SO₄, filtered andconcentrated to obtain the expected compound in the form of a solid.

¹H NMR (400 MHz, CDCl₃) δ ppm: 2.43 (s, 3H), 3.54-3.63 (m, 2H), 4.50(Is, 1H), 5.05-5.22 (m, 2H), 5.66-5.79 (m, 1H), 7.31 (d. J=8.1 Hz, 2H),7.76 (d, J=8.1 Hz, 2H)

Step B:4-Methyl-N-(2-methylprop-2-en-1-yl)-N-(prop-2-en-1-yl)benzene-1-sulphonamide

3-Chloro-2-methylpropene (20 mL, 0.20 mol) is added over a period of 5minutes to a suspension of4-methyl-N-(prop-2-en-1-yl)benzene-1-sulphonamide (27.9 g, 0.13 mol) andpotassium carbonate (28.1 g, 0.20 mol) in N,N-dimethylformamide (200 mL)cooled in an ice bath. After 20 minutes, the suspension is stirred atambient temperature for 18 hours. The suspension is concentrated todryness. The residue is taken up in ethyl acetate (250 mL) and water(110 mL). The aqueous phase is extracted with ethyl acetate (2×50 mL).The combined organic phases are washed successively with aqueous 3N HClsolution (50 mL), water (3×50 mL), aqueous 5% potassium bicarbonatesolution (50 mL), and finally brine (50 mL). The organic phase is driedover Na₂SO₄, filtered and concentrated to obtain the expected compoundin the form of an oil.

¹H NMR (400 MHz, CDCl₃) δ ppm: 1.69 (s, 3H), 2.43 (s, 3H), 3.70 (s, 2H),3.75-3.79 (m, 2H), 4.87 (d, J=25.1 Hz, 1H), 5.04-5.09 (m, 1H), 5.09-5.12(m, 1H), 5.45-5.59 (m, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.71 (d, J=8.1 Hz,2H)

Step C: 3-Methyl-1-(4-methylbenzenesulphonyl)-1H-pyrrole

A solution of the compound obtained in Step B (15.2 g, 57.3 mmol) intoluene (550 mL) is heated at 80° C. in the presence of(1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)-dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium(Grubbs' catalyst, 2nd generation) (150 mg, 0.18 trump for 1 hour.2,3-Dichloro-5,6-dicyano-p-benzoquinone (16.1 g, 70.9 mmol) is thenadded in one portion, and the solution is heated at 80° C. for 24 hours.The solution is filtered over Celite, and the filtrate is concentratedin vacuo. The product is purified by chromatography over silica gelusing ethyl acetate and heptane as eluants to obtain the expectedcompound in the form of a solid.

¹H NMR (400 MHz, CDCl₃) δ ppm: 2.02 (d, J=1.0 Hz, 3H), 2.39 (s, 3H),6.09-6.13 (m, 1H), 6.85-6.90 (m, 1H), 7.03-7.07 (m, 1H), 7.27 (d, J=8.4Hz, 2H), 7.72 (d, J 8.4 Hz, 2H)

Step D: 3-Methyl-1-(4-methylbenzenesulphonyl)-1H-pyrrole-2-carbonitrile

Aluminium chloride (19.4 g, 0.15 mol) is added all at once to a solutionof 3-methyl-1-(4-methylbenzenesulphonyl)-1H-pyrrole (13.0 g, 55.3 mmol)in 1,2-dichloroethane (230 mL) at ambient temperature. After stirringfor 20 minutes, cyanogen bromide (11.11 g, 0.10 mol) is added inportions over a period of 20 minutes. After 4.5 hours, an additionalamount of cyanogen bromide (1.94 g, 18.3 mmol) is added. After stirringfor 17 hours at ambient temperature, the reaction mixture is pouredslowly into a mixture of dichloromethane (300 mL) and water (600 mL)cooled to 0° C. The resulting mixture is stirred for 1 hour.Subsequently the phases are separated and the aqueous phase is extractedwith dichloromethane (3×150 mL). The combined organic phases are washedwith water (2×150 mL) and brine (150 mL). The organic phase is driedover Na₂SO₄, filtered and concentrated in vacuo to obtain the expectedcompound in the form of a solid.

¹H NMR (400 MHz, CDCl₃) δ ppm: 2.18 (s, 3H), 2.43 (s, 3H), 6.17 (d,J=3.2 Hz, 1H), 7.33-7.39 (m, 3H), 7.90 (d, J=8.5 Hz, 2H)

Step E:4-Bromo-3-methyl-1-(4-methylbenzenesulphonyl)-1H-pyrrole-2-carbonitrile

N-Bromosuccinimide (12.0 g, 67.4 mmol) is added all at once to asuspension of3-methyl-1-(4-methylbenzenesulphonyl)-1H-pyrrole-2-carbonitrile (14.45g, 55.6 mmol) in N,N-dimethylformamide (60 mL) at ambient temperature.The mixture is stirred at ambient temperature for 29 hours and is thencooled in an ice bath. Saturated aqueous sodium bisulphite solution (90mL), water (90 mL) and ethyl acetate (250 mL) are then added. The phasesare separated, and then the aqueous phase is extracted with ethylacetate (2×70 mL). The combined organic phases are washed with 5%aqueous potassium bicarbonate solution (90 mL), water (3×90 mL), andthen brine (3×90 mL). The organic phase is dried over Na₂SO₄, Filteredand concentrated in vacuo. The crude product is purified bychromatography over silica gel using toluene and heptane as eluants toobtain the expected compound in the form of a solid.

¹H NMR (400 MHz, CDCl₃) δ ppm: 2.13 (s, 3H), 2.45 (s, 3H), 7.38 (d,J=8.4 Hz, 2H), 7.43 (s, 1H), 7.92 (d, J=8.4 Hz, 2H)

Step F: 4-Bromo-1,3-dimethyl-1H-pyrrole-2-carbonitrile

Potassium hydroxide (3.65 g, 65.1 mmol) is added all at once to asuspension of4-bromo-3-methyl-1-(4-methylbenzenesulphonyl)-1H-pyrrole-2-carbonitrile(4.66 g, 13.7 mmol) in methanol (95 mL) cooled using an ice bath After15 minutes, the suspension is stirred at ambient temperature for 17hours. The methanol is evaporated to dryness. The evaporation residue istaken up in MTBE (25 mL) and washed with water (25 mL). The aqueousphase is extracted with MTBE (2×25 mL). The combined organic phases aredried over Na₂SO₄, filtered and concentrated in vacuo. The residueobtained is dissolved in tetrahydrofuran (50 mL) and the solution iscooled using an ice bath. NaH (60% in oil) (1.02 g, 25.5 mmol) is added.After 10 minutes, iodomethane (2.4 mL, 38.6 mmol) is also added. Themixture is stirred at ambient temperature for 1.5 hours. Thetetrahydrofuran is evaporated to dryness. The residue is taken up indichloromethane and washed with water. The aqueous phase is extractedwith dichloromethane. The combined organic phases are dried over Na₂SO₄,filtered and concentrated in vacuo to obtain the expected compound inthe form of a solid.

¹H NMR (400 MHz, CDCl₃) δ ppm: 2.16 (s, 3H), 3.71 (s, 3H), 6.74 (s, 1H)

Step G:4-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)-1,3-dimethyl-1H-pyrrole-2-carbonitrile

4-Bromo-1,3-dimethyl-1H-pyrrole-2-carbonitrile (2.03 g, 10.2 mmol) and4-[(tert-butyldimethylsilyl)oxy]aniline (3.41 g, 15.3 mmol) aredissolved in toluene (40 mL). The solution is degassed with nitrogen for10 minutes. Sodium tert-butylate (1.18 g, 12.2 mmol),2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.17 g, 0.41mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.187 g, 0.2 mmol)are then added. The mixture is heated at 100° C. for 30 minutes and thencooled to ambient temperature. Water (50 mL) and Celite (6 g) are added.The suspension is filtered over Celite, and the filtrate is diluted withMTBE. The phases are separated and the aqueous phase is extracted withMTBE (2×50 mL). The combined organic phases are dried over Na₂SO₄ andfiltered. The residue is purified by chromatography over silica gelusing ethyl acetate and heptane as eluants followed by reverse-phasechromatography using methanol and water as eluants. The product obtainedis lyophilised to provide the expected compound in the form of a solid.

¹H NMR (400 MHz, CDCl₃) δ ppm: 0.15 (s, 6H), 0.98 (s, 9H), 2.05 (s, 3H),3.70 (s, 3H), 4.69 (br. s, 1H), 6.55-6.57 (m, 2H), 6.64-6.69 (m, 3H)

¹³C NMR (100 MHz, CDCl₃) δ ppm: −4.37, 9.42, 18.27, 25.84, 35.50,102.59, 113.77, 115.13, 120.72, 121.91, 126.77, 126.94, 140.98, 148.39

Preparation 38″:4-[(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)amino]-1-ethyl-5-methyl-1H-pyrrole-2-carbonitrile

The procedure is in accordance with the process of Preparation 33″,replacing the iodomethane-d₃ in Step B by iodoethane.

¹H NMR (400 MHz, dmso-d6) δ ppm: 6.85 (s, 1H), 6.75 (s, 1H), 6.6/6.5(2d, 4H), 4 (quad, 2H), 2.1 (s, 3H), 1.3 (s, 3H), 0.9 (s, 9H), 0.1 (s,6H)

Preparation 39″:N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-2-ethoxy-pyrimidin-5-amineStep A: 5-Bromo-2-ethoxy-pyrimidine

5-Bromo-2-chloro-pyrimidine (5.0 g, 25 mmol) is dissolved in ethanol (55mL) and sodium ethylate (1.81 g, 26.6 mmol) is added in portions. Thereaction mixture is stirred for 15 hours at ambient temperature. Whenthe reaction is complete, the solvent is evaporated off, water (200 mL)is added, and then the reaction mixture is extracted with todichloromethane (2×100 mL). The organic phase is dried over Na₂SO₄, andthen evaporated to dryness to yield 5-bromo-2-ethoxy-pyrimidine.

Step B:N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-2-ethoxy-pyrimidin-5-amine

4-[tert-Butyl(dimethyl)silyl]oxyaniline (1.8 g, 8 mmol) and5-bromo-2-ethoxy-pyrimidine (1.6 g, 8 mmol) dissolved in anhydroustetrahydrofuran (30 mL) are stirred for 1 hour at ambient temperature inthe presence of sodium tert-butylate (4 mL, 2M solution in THF) andchloro(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)-phenyl]palladium(II)(111 mg, 0.16 mmol). The reaction mixture is filtered over Celite andthen evaporated to dryness. The residue is triturated in heptane toobtain the expected compound after filtration.

¹H NMR (500 MHz, dmso-d6, 300 K) δ ppm: 8.31 (s, 2H, pyrimidine-H), 7.80(s, 1H, NH), 6.73 (d, 2H, Ar—H), 6.68 (d, 2H, Ar—H), 4.26 (q, 2H,CH₂CH₃), 1.31 (t, 3H, CH₂CH₃), 0.94 (s, 9H, ^(t)Bu), 0.15 (s, 6H, Me)

IR: ν: aromatic: 1504 cm⁻¹; Si—C: 1247 cm⁻¹; C—O—C: 1057 cm⁻¹

Preparation 40″: tert-Butyl6-[(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)amino]-pyridin-3-yl carbonateStep A: 6-Bromopyridin-3-yl tert-butyl carbonate

To a solution of 5 g of 6-bromopyridin-3-ol (28.7 mmol) and 7.53 g ofdi-tert-butyl dicarbonate (34.5 mmol) in 50 mL of tetrahydrofuran thereis added 0.18 g of 4-dimethylaminopyridine (1.4 mmol). The mixture isstirred at ambient temperature for 6 hours and then concentrated. Theresidue obtained is dissolved in a mixture of ethyl ether and water.After separation of the phases, the separated-off organic phase is driedover MgSO₄ and concentrated to dryness. The title product is obtained inthe form of a solid which is used in the next Step without beingotherwise purified.

¹H NMR (400 MHz, dmso-d6) δ ppm: 8.4 (s, 1H), 7.71 (s, 2H), 1.5 (s, 9H)

Step B: tert-Butyl6-[(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)amino]pyridin-3-yl carbonate

To a solution of 2.79 g of the compound obtained in Step A (10.2 mmol)in 15 mL of toluene and 15 mL of tetrahydrofuran there are added 1.18 gof sodium tert-butylate (12.2 mmol), and then the batch is stirred underargon for 15 minutes. There is then added 0.35 g of palladium catalyst(0.5 mmol). The reaction mixture is then stirred at ambient temperaturefor 16 hours and then filtered. The filtrate is concentrated and takenup in a mixture of dichloromethane and water. The organic phase isseparated off and then washed with water, dried over MgSO₄, filtered andconcentrated to dryness. The crude product thereby obtained is purifiedby chromatography over silica gel using dichloromethane and ethylacetate as eluants. The residue is then taken up in a minimum ofisopropyl ether. The solid then obtained is filtered off, washed withether and then dried. The title product is obtained in the form of asolid, which is subsequently used without being otherwise purified.

¹H NMR (400 MHz, dmso-d6) δ ppm: 9 (s, 1H), 8.35 (wd, 1H), 8.3 (wd, 1H),8 (wd, 1H), 7.45 (dd, 1H), 7.45 (wd, 1H), 6.8 (d, 1H), 6.4 (wd, 1H), 3.8(s, 3H), 1.5 (s, 9H)

Preparation 41″: 3-[4-[tert-Butyl(dimethyl)silyl]oxyanilino]benzonitrile

The procedure is in accordance with the process of Preparation 1″,replacing the 4-bromo-1-methyl-1H-pyrazole used in Step B by3-bromobenzonitrile.

¹H NMR (400 MHz, dmso-d6) δ ppm: 8.3 (s, 1H), 7.3 (t, 1H), 7.2/7.1 (2dd, 2H), 7.15 (t, 1H), 7.05 (d, 2H), 6.8 (d, 2H), 0.95 (s, 9H), 0.2 (s,6H)

Preparation 42″:4-[4-[tert-Butyl(dimethyl)silyl]oxyanilino]thiophene-2-carbonitrile

The procedure is in accordance with the process of Preparation 1″,replacing the 4-bromo-1-methyl-1H-pyrazole used in Step B by4-bromothiophene-2-carbonitrile.

¹H NMR (400 MHz, dmso-d6) δ ppm: 8.35 (s, 1H), 7.59 (wd, 1H), 7.08 (wd,1H), 6.95 (d, 2H), 6.75 (d, 2H), 0.94 (s, 9H), 0.16 (s, 6H)

The amines NHR₃R₄ wherein R₃ and R₄, each independently of the other,represent an aryl or heteroaryl group are obtained in accordance withprocesses described in the literature (Surry D. S. et al., ChemicalScience, 2011, 2, 27-50, Charles M. D. et al., Organic Letters, 2005, 7,3965-3968). The reaction protecting the hydroxy function of the4-anilinophenol described in Preparation 2″ can be applied to varioussecondary amines NHR₃R₄ (as defined hereinbefore) having one or morehydroxy functions, when they are available commercially. Alternatively,the secondary amines having at least one hydroxy substituent may besynthesised directly in a protected form, i.e. starting from reagentswhose hydroxy function has been protected beforehand. Among theprotecting groups, tert-butyl(dimethyl)silyloxy and benzyloxy areespecially preferred.

Among the amines NHR₃R₄ having a hydroxy substituent that are used forsynthesising the compounds of the invention there may be mentioned:4-(4-toluidino)phenol, 4-(4-chloroanilino)phenol,4-(3-fluoro-4-methylanilino)phenol,4-[4-(trifluoromethoxy)anilino]-phenol, 4-[4-hydroxyanilino]phenol,{4-[(1-methyl-1H-indol-6-yl)amino]phenyl}methanol,4-(2,3-dihydro-1H-indol-6-ylamino)phenol,4-[(1-methyl-2,3-dihydro-1H-indol-6-yl)amino]phenol,4-[(1-methyl-1H-indol-6-yl)amino]phenol,4-[(1-methyl-1H-indol-6-yl)amino]cyclohexanol,4-[(1-methyl-1,2,3,4-tetrahydro-6-quinolinyl)amino]phenol,4-[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)amino]phenol,4-[4-(diethylamino)anilino]-phenol,4-(2,3-dihydro-1H-inden-5-ylamino)phenol,4-[(1-methyl-1H-indazol-5-yl)amino]-phenol,4-[(1t-methyl-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-5′-yl)amino]phenol,4-[(1,3,3-trimethyl-2,3-dihydro-1H-indol-5-yl)amino]phenol,4-[4-methoxy-3-(trifluoro-methyl)anilino]phenol,4-[4-(methylsulphanyl)-3-(trifluoromethyl)anilino]phenol,2-fluoro-4-[(1-methyl-1H-indol-5-yl)amino]phenol,4-[(1-ethyl-1H-indol-5-yl)amino]phenol,4-[(1-ethyl-2,3-dihydro-1H-indol-5-yl)amino]phenol,4-[(1-isopropyl-2,3-dihydro-1H-indol-5-yl)amino]phenol,4-(butylamino)phenol, 3-[(1-methyl-1H-indol-5-yl)amino]-1-propanol,4-[(1-methyl-1H-indol-5-yl)amino]-1-butanol,4-[(3-fluoro-4-methylphenyl)-amino]phenol,4-[(3-chloro-4-methylphenyl)amino]phenol,4-[(4-fluorophenyl)amino]-phenol,4-[(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)amino]phenol,4-[(4-fluorophenyl)-amino]phenol, 4-[(2-fluorophenyl)amino]phenol,4-[(3-fluorophenyl)amino]phenol, 4-[(2,4-difluorophenyl)amino]phenol,4-[(3,4-difluorophenyl)amino]phenol,3-[(4-hydroxy-phenyl)amino]benzonitrile,4-[(3-methoxyphenyl)amino]phenol, 4-[(3,5-difluorophenyl)-amino]phenol,4-[(3-methylphenyl)amino]phenol,4-[(4-hydroxyphenyl)amino]benzo-nitrite,4-[(3-chlorophenyl)amino]phenol, 4-(pyrimidin-2-ylamino)phenol,4-[(cyclobutyl-methyl)amino]phenol,2-[(4-hydroxyphenyl)amino]benzonitrile,4-{[(1-methyl-1H-pyrazol-4-yl)methyl]amino}phenol,4-[(cyclopropylmethyl)amino]phenol,4-{[(1-methyl-1H-pyrazol-3-yl)methyl]amino}phenol,4-(but-2-yn-1-ylamino)phenol, 4-(pyrazin-2-yl-amino)phenol,4-(pyridin-2-ylamino)phenol, 4-(pyridazin-3-ylamino)phenol,4-(pyrimidin-5-ylamino)phenol, 4-(pyridin-3-ylamino)phenol,4-[(3,5-difluoro-4-methoxyphenyl)-amino]phenol,4-(pyridin-4-ylamino)phenol, 4-[(3-fluoro-4-methoxyphenyl)amino]phenol,2-(phenylamino)pyrimidin-5-ol,5-[(4-hydroxyphenyl)amino]-2-methoxybenzonitrile,4-{[3-(trifluoromethyl)phenyl]amino}phenol and 4-(methylamino)phenol.The hydroxy function(s) of the secondary amines listed above is (are)protected beforehand by a suitable protecting group prior to anycoupling to an acid derivative of the compound of formula (VII) asdefined in the preceding general process.

Preparation I: tert-Butyl[2-(3-iodo-4-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)ethyl]carbamateStep A: 4-[2-(tert-Butoxycarbonylamino)ethyl]benzoic Acid

tert-Butyl dicarbonate (1.64 g; 7.5 mmol) is dissolved in 1,4-dioxane (5mL) and the solution is added to a well-stirred solution of4-(2-aminoethyl)benzoic acid (1.0 g; 5 mmol) in 1M aqueous sodiumhydroxide solution (25 mL) and 1,4-dioxane (10 mL), and the mixture isthen stirred at ambient temperature for 3 hours. The 1,4-dioxane isremoved by evaporation in vacuo, and then ethyl acetate (200 mL) isadded to the residue. The pH of the aqueous phase is adjusted to 1.5with 2M aqueous HCl solution. The organic phase is separated off and theaqueous phase is then extracted with ethyl acetate (100 mL). Thecombined organic extracts are washed with water, dried over Na₂SO₄ andevaporated to a volume of 10 mL. Heptane is added to the residue andthen the solid precipitate is filtered off to yield the title compound.

¹H NMR (500 MHz, dmso-d6, 300K): 12.81 (br s, 1H, COOH), 7.85 (m, 2H,Ar-2′ and 6′H), 7.31 (m, 2H, Ar-3′ and 5′H), 6.91 and 6.51 (2×br s, 1H,NH), 3.16 (m, 2H, CH₂), 2.75 (t, 2H, CH₂), 1.35 and 1.31 (2×br s, 9H,But); ¹³C NMR (125 MHz, dmso-d6, 300 K): 167.8 (q), 156.0 (CH), 145.3(q), 129.8 (2×CH), 129.3 (2×CH), 129.1 (q), 78.0 (q), 41.5 (CH₂), 35.9(CH₂), 28.7 (CH₃)

Step B: 4-[2-(tert-Butoxycarbonylamino)ethyl]-2-iodo-benzoic Acid

The compound of the above Step (0.88 g; 3.31 mmol), iodobenzenediacetate (1.07 g; 3.31 mmol), tetrabutylammonium iodide (1.22 g; 3.31mmol), iodine (0.84 g; 3.31 mmol) and diacetoxypalladium (0.04 g; 0.165mmol) are dissolved in 1,2-dichloroethane (8 mL), and the mixture isthen heated in a microwave reactor at 80° C. for 90 minutes. The cooledmixture is partitioned between saturated aqueous Na₂CO₃ solution (30 mL)and the original solvent. The organic phase is separated off and theaqueous residue is extracted with diethyl ether (2×15 mL). The pH of theresulting aqueous solution is adjusted to 2 with 2M aqueous HCl solutionand the product is then extracted with ethyl acetate (2×75 mL). Theorganic phase is dried over Na₂SO₄ and evaporated. The crude product ispurified by chromatography over silica gel to yield the mixture ofregioisomers, which are separated by preparative HPLC using water-TFAand acetonitrile as eluants. The pH of the appropriate combinedfractions is adjusted to 5 with NaHCO₃, and then the acetonitrile isevaporated off under reduced pressure. The precipitate is recovered byfiltration and then dried to yield the title compound.

¹H NMR (500 MHz, dmso-d6, 300K): 13.16 (broad s, 1H, COOH), 7.81 (s, 1H,Ar-3′H), 7.66 (d, 1H, Ar-6′H), 7.29 (d, 1H, Ar-5′H), 6.89 (t, 1H, NH),3.14 (t, 1H, CH₂), 2.69 (t, 1H, CH₂), 1.35 (s, 9H, Boc)

Step C: tert-Butyl[2-(3-iodo-4-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)ethyl]carbamate

The compound of the above Step (0.714 g; 1.82 mmol), TBTU (0.73 g; 2.28mmol), N-ethyl-N-isopropyl-propan-2-amine (0.94 mL; 5.46 mmol) andN,N-dimethylpyridin-4-amine (22 mg) are stirred in dichloromethane (20mL) for 5 minutes, and then (3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline(0.282 g; 1.92 mmol) (cf. Preparation 1′) is added. The mixture isstirred for three more hours. The reaction mixture is diluted withdichloromethane (150 mL) and then washed with water (25 mL), dried overNa₂SO₄ and evaporated. The crude product is purified by chromatographyover silica gel using dichloromethane and methanol as eluants to yieldthe title compound.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₂₄H₂₉IN₂O₃

[M+H]⁺ calculated: 521.1303

[M+H]⁺ measured: 521.1282

IR: ν: C—H: 2931 cm⁻¹; >C═O: 1706, 1627 cm⁻¹; amide: 1505 cm⁻¹; C—O—C:1248, 1166 cm⁻¹

Preparation H: tert-Butyl(4-Iodo-3-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}benzyl)carbamateStep A: 2-Iodo-5-methyl-benzoic Acid

3-Methylbenzoic acid (6.12 g; 45 mmol), iodobenzene diacetate (14.49 g;45 mmol), tetrabutylammonium iodide (16.62 g, 45 mmol), iodine (11.43 g;45 mmol) and diacetoxypalladium (0.5 g; 2.2 mmol) are dissolved in1,2-dichloroethane, and then the mixture is heated in a sealed tube at85° C. for 1 hour and 45 minutes. The cooled solution is purified bychromatography over silica gel using dichloromethane and methanol aseluants to yield the title compound.

Step B: Methyl 2-iodo-5-methyl-benzoate

The compound of the above Step (6.25 g, 23.9 mmol) is dissolved inanhydrous methanol (100 mL), and then SOCl₂ (3.6 mL, 49 mmol) is addeddropwise to the well-stirred solution. The solution is refluxed for 18hours and then evaporated to a volume of 25 mL and then poured intocrushed ice (100 g). The resulting mixture is extracted with diethylether (2×75 mL). The organic phase is washed with saturated aqueousNaHCO₃ solution and then brine, dried over Na₂SO₄ and evaporated todryness to yield the title compound.

Step C: Methyl 5-(bromomethyl)-2-iodo-benzoate

The compound of the above Step (5.7 g; 20.7 mmol), N-bromo-succinimide(3.67 g; 20.7 mmol) and dibenzoyl peroxide (0.24 g, 1 mmol) aredissolved in carbon tetrachloride (40 mL) and then refluxed for 5 hours.New portions of N-bromosuccinimide (1.0 g; 5.6 mmol) and dibenzoylperoxide (0.05 g; 0.2 mmol) are then added and heating is continued for4 more hours. The reaction mixture is cooled to ambient temperature. Theinsoluble parts are removed by filtration, and the concentrated filtrateis then purified by chromatography over silica gel using heptane andethyl acetate as eluants to yield the title compound.

Step D: Methyl 5-(aminomethyl)-2-iodo-benzoate

The compound of the above Step (0.53 g; 1.5 mmol) is dissolved in 7Mmethanolic ammonia (20 mL) and then stirred at ambient temperature for 1hour. The solution is evaporated to dryness to yield the title compound,which was used in the next Step without purification.

Step E: 5-[(tert-Butoxycarbonylamino)methyl]-2-iodo-benzoic Acid

Methyl 5-(aminomethyl)-2-iodo-benzoate hydrobromide (0.56 g; 1.5 mmol)was dissolved in pyridine (10 mL), then di-ten-butyl dicarbonate (0.80g; 3.6 mmol) is added and the mixture is stirred at ambient temperaturefor 30 minutes and then evaporated to dryness. The residue isredissolved in methanol (10 mL), and then 2M aqueous NaOH solution (3mL) and 2 mL of water are added. The resulting solution is stirred for 2hours at 50° C., then diluted with water (20 mL), and the methanol isevaporated off under reduced pressure. The pH of the resulting aqueoussolution is adjusted to 3 with 2M aqueous HCl solution; the product isthen extracted with ethyl acetate. The organic phase is washed withbrine, and then dried over Na₂SO₄ and evaporated to dryness. The crudeproduct is triturated with DCM. The solid formed is recovered byfiltration to yield the title compound.

¹H NMR (500 MHz, dmso-d6, 300 K): 13.24 (broad s, 1H, COOH), 7.91 (d,1H, Ar-3′H), 7.58 (d, 1H, Ar-6′H), 7.47 (t, 1H, NH), 7.09 (d, 1H,(Ar-5′H), 4.09 (d, 2H, CH₂), 1.38 (s, 9H, Boc); ¹³C NMR (125 MHz,dmso-d6, 300K): 168.6 (q), 156.3 (q), 141.1 (q), 140.9 (CH), 137.1 (q),131.6 (CH), 129.1 (CH), 92.2 (q), 78.5 (q), 28.7 (CH₃)

Step F: ten-Butyl(4-iodo-3-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-benzyl)carbamate

The compound of the above Step (1.62 g; 4.3 mmol), TBTU (2.76 g; 8.59mmol), N-ethyl-N-isopropyl-propan-2-amine (1.48 mL; 8.59 mmol) andN,N-dimethylpyridin-4-amine (10 mg) are stirred in DCM (50 mL) for 5minutes; (3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline (0.76 g; 5.15mmol) (cf. Preparation 1′) is then added and the mixture is stirred for15 minutes more. The insoluble parts arc removed by filtration, and thenthe concentrated filtrate is purified by chromatography over silica gelusing dichloromethane and methanol as eluants to yield the titlecompound.

Preparation III: tert-Butyl(3-bromo-4-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}benzyl)carbamateStep A: Methyl 4-(aminomethyl)-2-bromo-benzoate

A solution of methyl 2-bromo-4-(bromomethyl)benzoate (4.57 g; 14.84mmol) in 50 mL of methanol is added dropwise to a well-stirred solutionof ammonia in methanol (7M; 315 mL) at ambient temperature, and thesolution is then stirred for 3 hours. All the solvents are evaporatedoff and the residue is purified by chromatography over silica gel usingdichloromethane-methanol as eluants to yield the title compound.

Step B: 2-Bromo-4-[(tert-butoxycarbonylamino)methyl]benzoic Acid

The compound of the above Step (4.04 g; 16.6 mmol) is dissolved inpyridine (55 mL) and then di-tert-butyl dicarbonate (5.43 g; 24.9 mmol)is added and the mixture is stirred at ambient temperature for 16 hours;it is then evaporated to dryness. The residue is redissolved in methanol(100 mL), and then 1M aqueous NaOH solution (54 mL) is added. Theresulting solution is stirred for 1.5 hours at 50° C. and is thenallowed to cool to ambient temperature. The pH of the solution isadjusted to 7 using 2M aqueous HCl solution; the methanol is thenevaporated off under reduced pressure. The resulting aqueous solution isdiluted with water (50 mL), and then the pH is adjusted to 3 using 2Maqueous HCl solution. The product is extracted with dichloromethane(2×100 mL). The organic phase is washed with brine, then dried overNa₂SO₄ and evaporated to dryness to yield the title compound which isused in the next Step without purification.

IR: ν: N—H: 3359 cm⁻¹; C—H: 2983 cm⁻¹; >C═O: 1685, 1603 cm⁻¹; amide:1519 cm⁻¹; C—O—C: 1248, 1162, 1057 cm⁻¹

Step C: tert-Butyl(3-bromo-4-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}benzyl)carbamate

The compound of the above Step (3.7 g; 11.2 mmol), TBTU (7.19 g; 22.4mmol), N-ethyl-N-isopropyl-propan-2-amine (3.86 mL; 22.4 mmol) andN,N-dimethylpyridin-4-amine (48 mg) are stirred in dichloromethane (100mL) for 5 minutes, and then (3R)-3-methyl-1,2,3,4-tetrahydroisoquinoline(1.98 g, 13.44 mmol) (cf. Preparation 1′) is added, and the mixture isstirred for 1 hour more. The insoluble parts are removed by filtration,and then the concentrated filtrate is purified by chromatography oversilica gel using dichloromethane and methanol as eluants to yield thetitle compound.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₂₃H₂₇BrN₂O₃

[M+H]⁺ calculated: 459.1285

[M+H]⁺ measured: 459.1282

¹H NMR (500 MHz, dmso-d6, 300K, presence of amide rotamers): 7.66-6.87(m, 7H, aromatic), 5.34 and 4.12 (d, 2H, CH₂-isoquinoline), 5.02 and4.97 and 3.87 and 3.83 (m, 1H, CH₂-isoquinoline), 4.17 (d, 2H,CH₂-benzyl), 3.18-2.48 (m, 1H, CH₂-isoquinoline), 1.16 and 1.14 and 1.10and 0.98 (d, 3H, isoquinoline CH₃), 1.31 and 1.41 (s, 9H, Boc).

EXAMPLE 1

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

Step A: Ethyl5-(5-chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylate

To a solution of 1.4 g of the compound obtained in Preparation 1 (4.35mmol) in 50 mL of dichloromethane there are successively added 0.7 g ofthe compound obtained in Preparation 1 (4.79 mmol), 0.7 g of HOBT (5.22mmol), 0.81 g of EDC (5.22 mmol) and 1.6 mL of triethylamine (21.7mmol). The batch is then stirred overnight at ambient temperature. Thereaction mixture is then diluted with dichloromethane and washed 3 timeswith saturated aqueous NaHCO₃ solution. The organic phase is then driedover MgSO₄, filtered, concentrated to dryness, and then purified bychromatography over silica gel using dichloromethane and methanol aseluants.

¹H NMR: δ (500 MHz; dmso-d6; 300K): 7.6-7.3 (m, 3H, aromatic Hs,4-chlorophenyl); 7.2-6.85 (m, 4H, aromatic Hs, tetrahydroisoquinoline);6.45-6.3 (in, 1H, H pyrrole); 5.0-4.8-3.8 (m, 1H, aliphatic H,tetrahydroisoquinoline); 5.3-3.75 (dd, 2H, aliphatic Hstetrahydroisoquinoline); 4.2-4.0 (m, 2H, OCH₂CH₃); 3.25 (s, 3H,CH₃—N-pyrrole); 3.0-2.2 (m, 2H, aliphatic Hs, tetrahydroisoquinoline);2.5 (s, 3H, CH₃-pyrrole); 1.25 (t, 31-1, OCH₂CH₃); 1.05 (d, 3H,tetrahydroisoquinoline-CH₃)

IR: ν: >CD: 1693 cm⁻¹ ester; ν: >C═O: 1625 cm⁻¹ amide

Step B:5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylicAcid

To a solution of 1.7 g of the compound obtained in Step A (3.77 mmol) in5 mL of dioxane there is added 0.317 g of LiOH (7.5 mmol) dissolved in 5mL of water. The batch is heated in a microwave apparatus for 4 hours at100° C. (power 140 W). The reaction mixture is then Filtered andconcentrated to dryness. The residue thereby obtained is taken up indichloromethane (50 mL) and then saturated aqueous NH4Cl solution isadded thereto. The organic phase is washed with water and then withbrine, dried over MgSO₄, filtered and concentrated to dryness. The titleproduct is obtained in the form of a solid and is used directly in thenext Step.

¹H NMR: δ (500 MHz; dmso-d6; 300K): 11.05 (broad s, 1H, COOH), 7.5-7.2(m, 3H, aromatic Hs, 4-chlorophenyl); 7.2-6.9 (m, 4H, aromatic Hs,tetrahydroisoquinoline); 6.45-6.2 (m, 1H, aliphatic H, H pyrrole);5.3-3.75 (dd, 2H, aliphatic Hs, tetrahydroisoquinoline); 5.0-4.8-3.8 (m,1H, aliphatic H, tetrahydroisoquinoline); 3.5-3.2 (s, 3H,CH₃—N-pyrrole); 3.0-2.1 (aliphatic Hs, CH₃-tetraisoquinoline);2.5-2.4-1.98 (m, 3H, CH₃-pyrrole); 1.05-0.52 (m, 3H, aliphatic Hs,CH₃-tetraisoquinoline)

IR: ν: —OH: 3500-2000 cm⁻¹ carboxylic acid; ν: >C═O: 1699+1658 cm⁻¹carboxylic acid; ν: >C═N—: 1625 cm⁻¹ amide

Step C:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-5-(5-chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

To a solution of 0.65 g of the compound obtained in Step B (1.54 mmol)in 15 mL of dichloroethane there is added, dropwise, 0.244 mL of1-chloro-N,N,2-trimethyl-prop-1-en-1-amine. The reaction mixture isstirred at ambient temperature for 1 hour, and there are then added 0.56g of the compound of Preparation 1″ (1.84 mmol), 10 mL of dichloroethaneand 0.376 g of 4-dimethylaminopyridine (DMAP) (3.07 mmol). The batch isstirred at 110° C. overnight. The reaction mixture is concentrated,dissolved in dichloromethane and washed with saturated aqueous NaHCO₃solution. The title product is obtained in the form of an oil and isused directly in the next Step.

Step D:5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

To a solution of 0.8 g of the compound obtained in Step C (1.03 mmol) in2 mL of methanol, there are added 1.55 mL of a 1M solution of potassiumhydroxide in methanol (1.55 mmol). The batch is stirred at ambienttemperature for 30 minutes. The reaction mixture is then diluted withdichloromethane and successively washed with 1M aqueous HCl solution,saturated aqueous NaHCO₃ solution and then brine until neutral. Theorganic phase is then dried over MgSO₄, filtered and evaporated. Thecrude product thereby obtained is purified by chromatography over silicagel using dichloromethane and methanol as eluants. The solid therebyobtained is dissolved in a mixture of water/acetonitrile untildissolution is complete, filtered and then lyophilised.

Elemental microanalysis: (%, theoretical:measured)

% C=68.74:68.25; % H=5.43:5.69; % N=11.79:11.66; % Cl=5.97:5.95.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₄H₃₂ClN₅O₃

[M+H]⁺ calculated: 594.2266

[M+H]⁺ measured: 594.2289

EXAMPLE 2

5-(2-{[(3S)-3-(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1-methyl-N,N-diphenyl-1H-pyrrole-3-carboxamide

Step A: tert-Butyl{[(3S)-2-{2-[1-(diphenylcarbamoyl)-1-methyl-1H-pyrrol-2-yl]benzoyl}-1,2,3,4-tetrahydroisoquinolin-3-yl]methyl}carbamate

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 2 and tert-butyl[(3S)-1,2,3,4-tetrahydroisoquinolin-3-ylmethyl]carbamate (seePreparation 2′) in Step A, and N-phenylaniline in Step C.

Step B:5-(2-{[(3S)-3-(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1-methyl-N,N-diphenyl-1H-pyrrole-3-carboxamide

A solution of the NH-Boc compound of Step A in dichloromethane is placedat 0° C. 10 molar equivalents of trifluoroacetic acid are added theretodropwise. The batch is stirred at ambient temperature for 4 hours untilthe starting material has disappeared completely. The reaction mixtureis then concentrated to dryness, taken up again and co-evaporated twicewith toluene, then taken up in a mixture of acetonitrile/H₂O and finallylyophilised. The title product is then obtained after a neutralisationstep.

Elemental microanalysis: (%, theoretical:measured)

% C=77.75:77.27; % H=5.97:5.73; % N=10.36:10.44

EXAMPLE 3

5-(5-Chloro-2-{[(3S)-3-[(4-methylpiperazin-1-yl)methyl]-3,4-dihydro-isoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1H-indol-5-yl)-1-methyl-1H-pyrrole-3-carboxamide

Step A: tert-Butyl5-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl){[5-(5-chloro-2-{[(3S)-3-[(4-methylpiperazin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1-methyl-1H-pyrrol-3-yl]carbonyl}amino]-1H-indole-1-carboxylate

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 3 and(3S)-3-[(4-methyl-1-piperazinyl)methyl]-1,2,3,4-tetrahydro-isoquinoline(see Preparation 4′) in Step A, and the compound of Preparation 3″ inStep C.

Step B:5-(5-Chloro-2-{[(3S)-3-[(4-methylpiperazin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1H-indol-5-yl)-1-methyl-1H-pyrrole-3-carboxamide

To a solution of 455 mg (0.49 mmol) of the product obtained in Step A in5 mL of methanol there are added 135 mg (2.5 mmol) of KOH. Afterstirring for 3 hours at ambient temperature, the reaction mixture isconcentrated, treated with saturated aqueous NaHCO₃ solution andextracted with methylene chloride. The organic phase is then dried overMgSO₄, filtered and evaporated to dryness. The crude product therebyobtained is then purified by chromatography over silica gel usingdichloromethane and methanol as eluants to yield the expected product inthe form of a foam.

Elemental microanalysis: (%, theoretical:measured)

% C=70.72:68.54; % H=5.79:5.37; % N=11.78:11.41; % Cl=4.97:4.79.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₂H₄₁ClN₆O₃

[M+H]⁺ calculated: 713.3007

[M+H]⁺ measured: 713.2973

EXAMPLE 4

N-(4-Hydroxyphenyl)-N-(1H-indol-5-yl)-1-methyl-5-(6-{[(3S)-3-[(4-methylpiperazin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example3 using the compound of Preparation 4 in Step A.

Elemental microanalysis: (%, theoretical:measured)

% C=71.45:69.32; % H=5.86:5.22; % N=11.63:11.08.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₃H₄₂N₆O₅

[M+H]⁺ calculated: 723.3295

[M+H]⁺ measured: 723.3262

Unless otherwise mentioned, the compounds of the following Examples aresynthesised in accordance with the process of Example 1 using, in StepA: (i) the appropriate acid obtained according to one of Preparations 1to 32 and (ii) the appropriate tetrahydroisoquinoline compound obtainedaccording to one of Preparations 1′ to 9′ and, in Step C: (iii) thesuitable NHR₃R₄ amine (a non-exhaustive list is proposed in Preparations1″ to 42″. The compounds thereby obtained are optionally subjected to astep of conversion into salt form in the presence of HCl in ether. Afterfiltration and lyophilisation in a mixture of acetonitrile/water, thehydrochloride of the expected compound is obtained.

EXAMPLE 5

5-(5-Chloro-2-{[(3S)-3-[(4-methylpiperazin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-indol-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=64.54:64.9; % H=5.67:5.49; % N=10.5:10.4; % Cl=13.29:12.52; %Cl—−=8.86:7.39

EXAMPLE 6

5-(5-Chloro-2-{[(3S)-3-[(4-methylpiperazin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1-ethyl-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-1H-pyrrole-3-carboxamide.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₄H₄₅ClN₆O₃

[M+H]⁺ calculated: 741.3320

[M+H]⁺ measured: 741.3326

EXAMPLE 7

5-(5-Chloro-2-{[(3S)-3-[(4-methylpiperazin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1-cyclopropyl-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-1H-pyrrole-3-carboxamide

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₅H₄₅ClN₆O₃

[M+H]⁺ calculated: 7513320

[M+H]⁺ measured: 753.3306

EXAMPLE 8

5-(5-Chloro-2-{[(3S)-3-[(4-methylpiperazin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1-methyl-1H-indol-5-yl)-1-(propan-2-yl)-1H-pyrrole-3-carboxamide

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₅H₄₇ClN₆O₃

[M+H]⁺ calculated: 755.3476

[M+H]⁺ measured: 755.3466

EXAMPLE 9

N-(4-Hydroxyphenyl)-1-methyl-N-(1-methyl-1H-indol-5-yl)-5-(6-{[(3S)-3-[(4-methylpiperazin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=65.26:65.8; % H=5.73:5.47; % N=10.38:10.48; % Cl=8.76:8.46; %Cl−=8.76:8.02

EXAMPLE 10

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-phenyl-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=69.11:68.56; % H=5.8:5.31; % N=8.06:8.13; % Cl−=5.1:4.68

EXAMPLE 11

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-(3-hydroxypropyl)-2-methyl-N-phenyl-1H-pyrrole-3-carboxamidehydrochloride

Step A:1-[3-(Benzyloxy)propyl]-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-phenyl-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 10 and the compound of Preparation 3′ inStep A, and the compound of Preparation 2″ in Step C.

Step B:5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-(3-hydroxypropyl)-2-methyl-N-phenyl-1H-pyrrole-3-carboxamidehydrochloride

The compound of Step A is subjected to a deprotection reaction inaccordance with a protocol analogous to that described in Step B ofExample 23.

Elemental microanalysis: (%, theoretical:measured)

% C=68.24:67.96; % H=6:5.79; % N=7.58:7.61; % Cl−=4.8:4.75.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₂H₄₃FN₄O₅

[M+H]⁺ calculated: 703.3296

[M+H]⁺ measured: 703.33294

EXAMPLE 12

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-indazol-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=67.33:67.39; % H=5.65:5.18; % N=11.22:11.52; % Cl−=4.73:3.82

EXAMPLE 13

N-(3-Fluoro-4-methylphenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=66.97:66.72; % H=5.62:5.21; % N=7.44:7.59; % Cl−=4.71:4.54

EXAMPLE 14

N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-indazol-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=66.62:66.59; % H=5.59:4.67; % N=10.84:10.85; % Cl−=4.57:4.24

EXAMPLE 15

N-(4-Hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=68.28:67.07; % H=5.73:5.09; % N=7.77:7.75; % Cl−=4.92:5.71.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₁H₄₀N₄O₆

[M+H]⁺ calculated: 685.3026

[M+H]⁺ measured: 685.3033

EXAMPLE 16

N-(3-Fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=66.62:66.11; % H=5.45:5.2; % N=7.58:7.89; % Cl−=4.8:5.59

EXAMPLE 17

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-phenyl-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical: measured)

% C=67.51:66.91; % H=5.66:5.05; % N=7.87:7.88; % Cl−=4.98:5.75

EXAMPLE 18

1-(2-Hydroxyethyl)-N-(4-hydroxyphenyl)-2-methyl-5-(6-{[(3S)-3-[2-(morpholin-4-yl)ethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-1H-pyrrole-3-carboxamidehydrochloride

Step A:1-[2-(Benzyloxy)ethyl]-N-[4-(benzyloxy)phenyl]-2-methyl-5-(6-{[(3S)-3-[2-(morpholin-4-yl)ethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 9 and(3S)-3-[2-(morpholin-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline (seePreparation 5′) in Step A, and 4-(bentyloxy)-N-phenylaniline (seePreparation 8″) in Step C.

Step B:1-(2-Hydroxyethyl)-N-(4-hydroxyphenyl)-2-methyl-5-(6-{[(3S)-3-[2-(morpholin-4-yl)ethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-1H-pyrrole-3-carboxamidehydrochloride

The compound of Step A is subjected to a deprotection reaction inaccordance with a protocol analogous to that described in Step B ofExample 23.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₈H₄₀N₆O₅

[M+H]⁺ calculated: 729.3283

[M+H]⁺ measured: 729.3282

EXAMPLE 19

N-(4-Hydroxyphenyl)-5-(5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-phenyl-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=69.63:69.45; % H=6.13:5.94; % N=7.92:7.79; % Cl−=5.01:4.58

EXAMPLE 20

N-(4-Hydroxyphenyl)-5-(5-methoxy-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(pyridin-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=69.39:69.66; % H=5.66:5.46; % N=8.99:8.92; % Cl−=5.69:5.29.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₆H₃₅N₄O₄

[M+H]⁺ calculated: 587.2653

[M+H]⁺ measured: 587.2649

EXAMPLE 21

N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-2,3-dihydro-1,4-benzodioxin-6-yl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=64.99:64.67; % H=5.86:5.67; % N=11.37:11.27; % Cl−=4.8:4.71.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₄₃N₆O₆

[M+H]⁺ calculated: 703.3236

[M+H]⁺ measured: 703.3239

EXAMPLE 22

N-(4-Hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-2,3-dihydro-1,4-benzodioxin-6-yl)-N-phenyl-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=68.61:67.97; % H=5.89:5.59; % N=7.62:7.55; % Cl−=4.82:4.27.

EXAMPLE 23

1-(2-Hydroxyethyl)-N-(4-hydroxyphenyl)-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

Step A:1-[2-(Benzyloxy)ethyl]-N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example1 using the acid to of Preparation 9 and the compound of Preparation 1″in Step C.

Step B:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-1-(2-hydroxyethyl)-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

To a solution of 6.86 g (8.19 mmol) of the compound of Step A in 70 mLof anhydrous methanol there are added 1.37 g of Pd/C 10%. The batch isdegassed for 0.5 hours and then stirred at ambient temperature underdihydrogen pressure (1.5 bar) for 12 hours. The reaction mixture is thenfiltered and then concentrated to dryness. The expected product isobtained in the form of a solid.

¹H NMR: δ (500 MHz; dmso-d6; 300K): 7.7-7.4 (s, 1H, H pyrazole); 7.1-6.8(s, 1H, H pyrazole); 7.3-6.9 (m, 4H, aromatic Hs, Htetrahydroisoquinoline); 7.0-6.7 (m, 2H, aromatic Hs); 6.9-6.4 (m, 2H,aromatic Hs); 6.8-6.4 (m, 2H, aromatic Hs); 6.1 (m, 2H, OCH₂O); 5.2,5.0, 4.7 (4s, H, H-pyrrole (presence of conformational isomers); 5.15(d, 1H, aliphatic H, H tetrahydroisoquinoline); 4.9 (m, 1H, aliphatic H,H tetrahydroisoquinoline); 4.9-4.8 (m, 1H, CH₂OH); 4.7 (m, 1H, aliphaticH, H tetrahydroisoquinoline); 3.9 (d, 1H, aliphatic H, Htetrahydroisoquinoline); 3.85 (m, 1H, aliphatic H, Htetrahydroisoquinoline); 3.7 (m, 2H, aliphatic Hs, CH₂CH₂OH); 3.75 (2s,3H,); 3.5-3.2 (m, 2H, aliphatic Hs, CH₂CH₂OH); 3.0-2.4 (m, 2H, aliphaticH, H tetrahydroisoquinoline); 2.4-2.3 (4s, 3H, CH₃-pyrrole); 1.5, 0.95,0.75 (4 d, 3H, CH₃-THIQ); 0.85 (broad s, 9H, Si(CH₃)₂(CH(CH₃)₂); 0.15(m, 6H, Si(CH₃)₂(CH(CH₃)₂)

IR: ν: —OH: 3346 cm⁻¹ carboxylic acid; ν: >C═O: 1621 cm⁻¹

Step C:1-(2-Hydroxyethyl)-N-(4-hydroxyphenyl)-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

The phenol function of the compound of Step B is deprotected followingthe process of Step D of Example 1.

Elemental microanalysis: (%, theoretical:measured)

% C=68.23:68.12; % H=5.57:5.29; % N=11.05:10.79.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₆H₃₆N₅O₆

[M+H]⁺ calculated: 634.2662

[M+H]⁺ measured: 634.2660

EXAMPLE 24

N-(4-Hydroxyphenyl)-5-(5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=65.86:64.47; % H=6.09:5.88; % N=11.82:11.45; % Cl−=4.98:6.7.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₉H₄₂N₆O₅

[M+H]⁺ calculated: 675.3289

[M+H]⁺ measured: 675.3287

EXAMPLE 25

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=63.77:62.83; % H=5.63:5.83; % N=11.74:11.29; % Cl−=4.95:5.42

EXAMPLE 26

N-(4-Hydroxyphenyl)-2-methyl-1-[2-(methylamino)ethyl]-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

The procedure is in accordance with Steps A, B and C of the process ofExample 30 replacing the sodium azide used in Step B by methylamine.After purification over silica gel (CH₂Cl₂/MeOH/NH₃ gradient), thecompound obtained, 0.3 g (0.46 mmol), is dissolved in 5 mL of anhydrousmethanol and there is added, dropwise, 0.464 mL (0.47 mmol) of 1M HClsolution in ether. The batch is stirred for 0.5 hours at ambienttemperature. The precipitate thereby obtained is filtered off and driedand then dissolved in a mixture of CH₃CN/H₂O before being lyophilised atlow temperature. The expected product is obtained in the form of asolid.

Elemental microanalysis: (%, theoretical:measured)

% C=65.05:64.64; % H=5.75:5.43; % N=12.3:12.3; % Cl−=5.19:5.39.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₇H₃₈N₆O₅

[M+H]⁺ calculated: 647.2903

[M+H]⁺ measured: 647.2922

EXAMPLE 27

1-[2-(Dimethylamino)ethyl]-N-(4-hydroxyphenyl)-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

The procedure is in accordance with the process of Example 26, replacingthe methylamine in Step B by dimethylamine.

Elemental microanalysis: (%, theoretical:measured)

% C=65.46:65.07; % H=5.93:5.87; % N=12.05:12.06; % Cl−=5.08:5.55.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₈H₄₀N₆O₅

[M+H]⁺ calculated: 661.3060

[M+H]⁺ measured: 661.3045

EXAMPLE 28

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(pyridin-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=66.99:66.88; % H=5.14:5.28; % N=8.93:8.87; % Cl−=5.65:4.98.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₅H₃₂C₁N₄O₃

[M+H]⁺ calculated: 591.2157

[M+H]⁺ measured: 591.2178

EXAMPLE 29

5-(5-Chloro-2-{[(3S)-3-{[2-(morpholin-4-yl)ethoxy]methyl}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-phenyl-1H-pyrrole-3-carboxamidehydrochloride

Step A: Methyl5-(5-chloro-2-{[(3S)-3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylate

To a solution of 4.9 g of the compound of Preparation 1 in a mixture of40 mL of dimethylformamide and 40 mL of tetrahydrofuran there are added2.73 g (1.1 equivalents) of(3S)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline, 7.95 mL ofdiisopropylethyl-amine and 9.84 g (1.7 equivalents) of HATU. Afterstirring for 2 hours at ambient temperature, the reaction mixture isdried, taken up in ethyl acetate and then washed with 10% aqueous citricacid solution and water. The combined aqueous phases are extracted withethyl acetate. The organic phases thereby obtained are combined, driedover Na₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct obtained is purified by chromatography over silica gel usingdichloromethane and ethanol as eluants to yield the title compound.

¹H NMR: δ (500 MHz; dmso-do; 300K): 7.6-7.4 (m, 3H, Cl-Ph); 7.2-6.9 (m,4H, Ar(THIQ); 6.5-6.15 (broad 4s, 1H, pyrrole); 4.9-3.8 (6 d, 2H, NCH₂THIQ); 4.85-3.6 (m, 1H, NCH THIQ); 4.2-4.0 (m, 2H, OCH₂ ester), 3.45-3.2(3s, 3H, N—CH₃); 3.35-3.0 (3m, 2H, HOCH₂); 3.0-2.0 (m, 2H, THIQ);2.5-2.1 (m, 3H, CH₃ pyrrole); 1.25-1.1 (m, 3H, CH₃ ester)

IR: ν —OH: 3388 cm⁻¹, ν 1693 cm⁻¹ (conjugated ester), ν>C═O: 1620 cm⁻¹(amide)

Step B: Methyl5-(5-chloro-2-{[(3S)-3-{[2-(morpholin-4-yl)ethoxy]methyl}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylate

A solution of 1.7 g (3.2 mmol) of the compound obtained in the aboveStep in 20 mL of dimethylformamide is added, dropwise at 0° C., to asuspension of 0.280 g of NaH 60% in oil (2.2 equivalents) in 10 mL ofdimethylformamide. After stirring for 5 minutes at ambient temperature,a suspension of 0.68 g of 4-(2-bromoethyl)morpholine hydrobromide (1.1equivalents) is added dropwise. The reaction mixture is stirred atambient temperature for 45 minutes. There are then added, in two stepsover 20 hours, 2.2 equivalents of 4-(2-bromoethyl)morpholinehydrobromide, and then 3 equivalents of NaH 60% in oil. The reactionmixture is then poured into a mixture of 10% aqueous ammonium chlorideand ethyl acetate. The resulting organic phase is successively washedwith water, and then with saturated aqueous LiCl solution and brine. Itis then dried over Na₂SO₄, filtered and concentrated under reducedpressure. The oil obtained is purified by chromatography over silica gelusing dichloromethane and ethanol as eluants to provide the expectedproduct.

¹H NMR: δ (500 MHz; dmso-d6; 300K): 7.6-7.3 (m, 3H, Cl-Ph); 7.2-6.85 (m,4H, Ar(THIQ); 6.5-6.15 (broad s, 1H, pyrrole); 5.25-3.8 (m, 2H, NCH₂THIQ); 5.05-3.75 (m, 1H, NCH THIQ); 4.2-4.0 (m, 2H, OCH₂ ester),3.5-3.25 (m, 3H, N—CH₃); 3.6-2.75 (m, 8H, OCH₂ morpholinoethoxymethyl);2.95-2.05 (m, 2H, THIQ); 2.55-2.15 (m, 6H, NCH₂ morpholinoethoxymethyl);2.55-2.05 (m, 3H, CH₃ pyrrole), 1.25-1.1 (m, 3H, CH₃ ester)

IR: ν>C═O: 1694 cm⁻¹ (conjugated ester), ν>C═O: 1629 cm⁻¹ (amide)

Step C:5-(5-Chloro-2-{[(3S)-{[2-(morpholin-4-yl)ethoxy]methyl}-3,4-dihydro-isoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylicAcid

To a solution of 1.46 g of the compound of the above Step in 5 mL ofdioxane there are added 5 mL of 1M aqueous LiOH solution. The batch isheated in a microwave apparatus (100 W) at 100° C. for 2 hours. Thereaction mixture is poured into water and then extracted with ethylether. The ethereal phase is extracted again with 10 mL of water. Theaqueous phases are acidified to pH 5-6 by adding saturated aqueousammonium chloride solution and then extracted twice withdichloromethane. The dichloromethane phase is dried over Na₂SO₄,filtered and concentrated to dryness. The title product is obtained inthe form of a meringue.

¹H NMR: δ (500 MHz; dmso-d6; 300K): 11.4 (broad s, 1H, CO₂H), 7.6-7.3(m, 3H, Cl-Ph); 7.2-6.8 (m, 4H, Ar(THIQ); 6.5-6.2 (broad 4s, 1H,pyrrole); 5.25-3.75 (m, 2H, NCH₂ THIQ); 5.05-3.7 (3m, 1H, NCH THIQ);3.5-3.2 (3s, 3H, N—CH₃); 3.6-2.7 (m, 8H, OCH₂ morpholinoethoxymethyl);2.5-2.2 (m, 6H, NCH₂ morpholinoethoxymethyl); 3.0-2.0 (m, 2H, THIQ),2.5-2.0 (3s, 3H, CH₃ pyrrole)

IR: ν —OH: 3300-2200 cm⁻¹, ν>C═O: 1697-1662 cm⁻¹ (double band,carboxylic acid), ν>C═O: 1628 cm⁻¹ (amide)

Step D:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-5-(5-chloro-2-{[(3S)-3-{[2-(morpholin-4-yl)ethoxy]methyl}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-phenyl-M-pyrrole-3-carboxamide

The acid obtained in Step C (1.48 g) is suspended in 15 mL of1,2-dichloroethane. 1.1 equivalents of1-chloro-N,N,2-trimethylpropenylamine are added thereto. After stirringfor 1 hour at ambient temperature, there are added 15 mL of toluene and1.05 equivalents of the compound of Preparation 2″. The reaction mixtureis heated for 14 hours at 110° C. and then dried. The crude productthereby obtained is purified by chromatography over silica gel usingdichloromethane and ethanol as eluants to yield the expected product.

¹H NMR: 3 (500 MHz; dmso-d6; 300K): 7.55-7.25 (m, 3H, Cl-Ph); 7.25-6.6(m, 9H, Ar(THIQ)+phenyl); 6.8-6.5 (m, 2H, phenoxy); 7.0-6.6 (m, 2H,phenoxy); 5.7-5.05 (broad 4s, 1H, pyrrole); 5.2-3.6 (8d, 2H, THIQ);5.05-3.6 (4m, 1H, NCH THIQ), 3.6-2.9 (m, 8H, aliphaticmorpholinoethoxymethyl); 3.4-3.2 (broad 3s, 3H, N—CH₃); 3.0-2.1 (m, 2H,THIQ), 2.35 (m, 2H, NCH₂ morpholinoethoxymethyl); 2.4-2.2 (m, 4H, NCH₂morpholine); 2.4-2.15 (broad 3s, 3H, CH₃ pyrrole); 0.8 (broad 2s, 9H,SiC(CH₃)₃); 0.1 (4s, 6H, SiCH₃)

IR: ν>C═O: 1635-1595 cm⁻¹ (double band), ν Si—O: 1117 cm⁻¹, ν Si—C: 837cm⁻¹

Step E:5-(5-Chloro-2-{[(3S)-3-{[2-(morpholin-4-yl)ethoxy]methyl}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-phenyl-1H-pyrrole-3-carboxamidehydrochloride

To a solution of 0.7 g of the compound of Step D in 5 mL of methanolthere is added 0.92 mL of a 1M solution of potassium hydroxide inmethanol. After stirring for 1 hour 10 minutes at ambient temperature,saturated aqueous sodium bicarbonate solution is added. The productwhich precipitates is extracted with ethyl acetate and then washed withwater and brine. The resulting aqueous phases are extracted again withethyl acetate. The organic phases thereby obtained are dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct obtained is purified by chromatography over silica gel usingdichloromethane and ammonia-in-ethanol as eluants to provide 0.536 g ofthe title product, in the form of the base. The latter is dissolved inacetonitrile and converted into salt form using 1 M aqueous HClsolution. After a lyophilisation step, the expected product is obtainedin the form of a solid.

Elemental microanalysis: (%, measured(theoretical)

% C=66.4 (66.75); % H=5.98 (5.87); % N=7.38 (7.41); % Cl=9.42 (9.38); %Cl.=4.57 (4.69).

EXAMPLE 30

1-(2-Aminoethyl)-N-(4-hydroxyphenyl)-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

Step A:2-{3-[(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)(1-methyl-1H-pyrazol-4-yl)carbamoyl]-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrol-1-yl}ethylmethanesulphonate

A solution of 4.65 g of the compound obtained in Step B of Example 23(6.22 mmol) in 100 mL of anhydrous THF is placed at 0° C. There aresuccessively added thereto 3.5 mL (12.44 mmol) of triethylamine andthen, dropwise, 0.722 mL of methanesulphonic chloride (9.33 mmol)dissolved in 20 mL of THF. The batch is then stirred at ambienttemperature for 2 hours. The reaction mixture is hydrolysed by additionof saturated aqueous NaHCO₃ solution and then extracted twice with ethylacetate. The organic phases are combined, dried over MgSO₄ andconcentrated to dryness. The expected compound is obtained in the formof a glassy solid.

¹H NMR: δ (500 MHz; dmso-d6; 300K): 7.7-7.45 (s, 1H, H pyrazole);7.1-6.9 (s, 1H, H pyrazole); 7.2-6.4 (m, 8H, aromatic Hs); 6.95-6.65 (m,2H, aromatic Hs); 6.1 (m, 2H, OCH₂O); 5.2, 4.6 (4s, H, H-pyrrole(presence of conformational isomers); 4.9, 4.6, 3.9, 3.8 (m, 1H),5.05-3.75 (m, 1H, aliphatic H, H tetrahydroisoquinoline); 4.3-4.05 (m,2H, aliphatic Hs, CH₂CH₂OSO₂CH₃); 4.2-3.95 (m, 2H, aliphatic Hs,CH₂CH₂OSO₂CH₃); 3.75-2.7 (2s, 3H, CH₃-pyrazole); 3.0 (several s, 3H,CH₂OSO₂CH₃); 3.05-2.5 (several m, 2H, aliphatic Hs, Htetrahydroisoquinoline); 2.45-2.3 (several s, 3H, CH₃-pyrrole); 1.05,0.75 (several d, 3H, CH₃-tetraisoquinoline); 0.9 (several s, 9H,Si(CH₃)₂(CH(CH₃)₂); 0.1 (m, 6H, Si(CH₃)₂(CH(CH₃)₂)

IR: ν: >C═O: 1626 cm⁻¹, ν: —SO₂: 1349 and 1172 cm⁻¹

Step B:1-(2-Azidoethyl)-N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

To a solution of 2 g (2.42 mmol) of compound of Step A in 20 mL ofanhydrous DMF there is added 0.472 g (7.26 mmol) of sodium azide. Thebatch is stirred at 65° C. for 4 hours 30 minutes. The reaction mixtureis poured into saturated aqueous NaHCO₃ solution and then extractedtwice with ethyl acetate. The organic phases are combined and washedwith saturated aqueous LiCl solution, dried over MgSO₄ and concentratedto dryness. After purification over silica gel using dichloromethane andammonia-in-methanol as eluants, the expected product is obtained in theform of a foam.

¹H NMR: δ (500 MHz; dmso-d6; 300K): 7.65-7.45 (several s, 1H, Hpyrazole); 7.1-6.9 (several s, 1H, H pyrazole); 7.3-6.4 (several m, 6H,aromatic Hs); 7.1-6.9 (several s, 1H, aromatic Hs); 6.8, 6.5 (2m, 2H,aromatic Hs); 6.1 (several s, 2H, OCH₂O); 5.25-4.65 (several s, 1H,H-pyrrole (presence of conformational isomers); 4.9, 4.6, 3.8 (severalm, 1H); 5.05-3.7 (several m, 4H, aliphatic Hs, H-THIQ CH₂CH₂N₃); 3.7(several s, 31-1, H CH₃-pyrazole); 3.5-3.25 (m, 2H, CH₂CH₂N₃); 3.1-2.4(several in, 3H, CH₃-pyrrole); 2.45-2.3 (several s, 3H, CH₃-pyrrole);1.0-0.75 (several d, 3H, CH₃-THIQ); 0.9 (several s, 9H,Si(CH₃)₂(CH(CH₃)₂); 0.1 (several s, 6H, Si(CH₃)₂(CH(CH₃)₂)

IR: ν: —N═N═N: 2100 cm⁻¹, ν: >C═O: 1630 cm⁻¹, ν: —Si—O—: 1035 cm⁻¹

Step C:1-(2-Azidoethyl)-N-(4-hydroxyphenyl)-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

To a solution of 1.12 g of the compound obtained in Step B (14.49 mmol)in 5 mL of methanol there are added, dropwise, 7.24 mL of 1M methanolicpotassium hydroxide solution (72.45 mmol). The batch is stirred atambient temperature for 3 hours. The reaction mixture is thenconcentrated to dryness, taken up in dichloromethane, hydrolysed withsaturated aqueous NaHCO₃ solution and then extracted twice withdichloromethane. The organic phases are then combined, washed withwater, dried over MgSO₄ and concentrated to dryness. The expectedproduct is obtained in the form of a foam and used directly in the nextStep.

¹H NMR: δ (500 MHz; dmso-d6; 300K): 9.60 ((s, 1H, CH₂CH₂OH); 7.65-7.45(several s, 1H, H pyrazole); 7.1-6.9 (several s, 1H, H pyrazole);7.3-6.4 (several m, 6H, aromatic Hs); 7.1-6.9 (several s, 1H, aromaticHs); 6.8, 6.5 (2m, 211, aromatic Hs); 6.15 (several s, 2H, OCH₂O);5.35-4.8 (several s, 1H, H-pyrrole (presence of conformational isomers);4.9, 4.6, 3.8 (several in, 1H, aliphatic H, H tetrahydroisoquinoline);3.7 (several s, 3H, H CH₃-pyrazole); 3.5-3.25 (m, 2H, CH₂CH₂N₃); 3.1-2.4(several m, 3H, CH₃-pyrrole); 2.45-2.3 (several s, 3H, H THIQ); 2.45-2.3(several s, 3H, CH₃-pyrrole); 1.0-0.75 (several d, 3H, CH₃-THIQ)

IR: ν: —OH: 3171 cm⁻¹, ν: —N═N═N: 2100 cm⁻¹, ν: >C═O: 1617 cm⁻¹

Step D:1-(2-Aminoethyl)-N-(4-hydroxyphenyl)-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

To a solution of 1.27 g of the compound obtained in the above Step (1.93mmol) in 15 mL of anhydrous ethanol there is added 0.154 g of Pd/C 10%.The batch is degassed for 0.5 hours. It is then stirred for 12 hours atambient temperature under hydrogen pressure (1.5 bar). The reactionmixture is then filtered and then concentrated to dryness. Afterpurification by chromatography over silica gel (CH₂Cl₂/MeOH/NH₃gradient), an oily residue is obtained. The residue is dissolved in 10mL of anhydrous ethanol and then converted into salt form by adding twomolar equivalents of a 1N solution of HCl in ethanol. The product isthen dried before being dissolved in a minimum of a mixture of water andacetonitrile. After a lyophilisation step at low temperature, theexpected product is obtained in the form of a solid.

Elemental microanalysis: (%, theoretical:measured)

% C=64.62:63:84; % H=5.57:5.55; % N=12.56:12.36; % Cl−=5.3:5.56.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₆H₃₆N₆O₅

[M+H]⁺ calculated: 633.2820

[M+H]⁺ measured: 633.2808

EXAMPLE 31

N-(4-Hydroxyphenyl)-5-(5-methoxy-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

Elemental microanalysis: (%, theoretical:measured)

% C=71.29:70.17; % H=5.98:5.98; % N=11.88:11.49.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₅H₃₆N₅O₄

[M+H]⁺ calculated: 590.2762

[M+H]⁺ measured: 590.2778

EXAMPLE 32

Phenyl(4-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-3-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}benzyl)-carbamate

Step A: N-(4-Benzyloxyphenyl)-N,1,2-trimethyl-pyrrole-3-carboxamide

The process is analogous to that described in Step A of Example 45.

Step B: tert-Butyl[4-(4-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-1,5-dimethyl-1H-pyrrol-2-yl)-3-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}benzyl]-carbamate

The compound of Preparation 11 (1.5 g; 2.96 mmol) and the compound ofStep A (1.16 g; 3.44 mmol) are dissolved in dimethylacetamide (25 mL)and then nitrogen is bubbled through the solution for 5 minutes.Potassium acetate (0.586 g; 5.92 mmol) andbis(triphenylphosphine)palladium(II) dichloride (0.2 g; 0.295 mmol) areadded to the mixture which is then heated to 100° C. and, after stirringfor 20 minutes, water (10 μL) is added. Stirring at 100° C. under anitrogen atmosphere is continued for 2 hours more. The reaction mixtureis allowed to cool to ambient temperature and is then evaporated to avolume of 15 mL. The resulting mixture is filtered over a short Celitecolumn and then purified by preparative HPLC using water-TFA andacetonitrile as eluants. The pH of the appropriate fractions is adjustedto 7 with NaHCO₃, and then the acetonitrile is evaporated off underreduced pressure. The aqueous residue is extracted with DCM. The organicphase is washed with brine, dried over Na₂SO₄ and evaporated to drynessto yield the title compound.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₄₁N₅O₄

[M+H]⁺ calculated: 713.3705

[M+H]⁺ measured: 713.3709

Step C:5-[4-(Aminomethyl)-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl]-N-[4-(benzyloxy)phenyl]-N,1,2-trimethyl-1H-pyrrole-3-carboxamidehydrochloride

The compound of the above Step (1.18 g, 1.66 mmol) isdissolved/suspended in 4M HCl in dioxane (20 mL). The heterogeneousmixture is stirred for 30 minutes at ambient temperature and thenevaporated to dryness to yield 1.19 g of the title compound which isused in the next Step without purification.

Step D: Phenyl(4-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-3-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}benzyl)carbamate

The title compound is obtained starting from the compound of the aboveStep in accordance with the protocol of Step D of Example 45.

Elemental microanalysis: (%, measured(theoretical))

% C=72.83 (72.88); % H=6.01 (5.96); % N=8.02 (8.72).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₉H₃₈N₄O₅

[M+H]⁺ calculated: 643.2922

[M+H]⁺ measured: 643.2916

EXAMPLE 33

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, measured(theoretical))

% C=65.75 (65.84); % H=5.38 (5.39); % N=7.62 (7.68); % Cl=9.77 (9.72); %Cl=4.84 (4.86)

EXAMPLE 34

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, measured(theoretical))

% C=65.61 (65.84); % H=5.09 (5.39); % N=7.76 (7.68); % Cl−=4.83 (4.86)

EXAMPLE 35

N-(4-Hydroxyphenyl)-N,1,2-trimethyl-5-(2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-4-{[(phenoxyacetyl)amino]methyl}phenyl)-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example32 using 2-phenoxyacetyl chloride as acylating agent in Step D.

Elemental microanalysis: (%, measured(theoretical))

% C=72.53 (73.15); % H=5.76 (6.14); % N=8.31 (8.53)

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₄₀N₄O₅

[M+H]⁺ calculated: 657.3079

[M+H]⁺ measured: 657.3061

EXAMPLE 36

5-(4-{[(Ethylcarbamoyl)amino]methyl}-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example32 using ethyl isocyanate as acylating agent in Step D.

Elemental microanalysis: (%, measured(theoretical))

% C=70.88 (70.8); % H=6.02 (6.62); % N=11.17 (11.8).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₅H₃₉N₅O₄

[M+H]⁺ calculated: 594.3100

[M+H]⁺ measured: 594.3083

EXAMPLE 37

5-(4-{[(Benzylcarbamoyl)amino]methyl}-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example32 using benzyl isocyanate as acylating agent in Step D.

Elemental microanalysis: (%, measured(theoretical))

% C=73.21 (73.26); % H=5.98 (6.3); % N=10.23 (10.68).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₄₁N₅O₄

[M+H]⁺ calculated: 656.3239

[M+H]⁺ measured: 656.3256

EXAMPLE 38

5-(5-Chloro-2-{[(3S)-3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-phenyl-1H-pyrrole-3-carboxamide

Elemental microanalysis: (%, measured(theoretical))

% C=70.97 (71.34); % H=5.2 (5.32); % N=6.96 (6.93)

EXAMPLE 39

N-(4-Hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

Elemental microanalysis: (%, measured(theoretical))

% C=69.81 (69.64); % H=5.6 (5.51); % N=11.55 (11.6).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₅H₃₄N₅O₅

[M+H]⁺ calculated: 604.2554

[M+H]⁺ measured: 604.2565

EXAMPLE 40

Phenyl(3-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-4-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}benzyl)-carbamate

Step A: N-(4-Benzyloxyphenyl)-N,1,2-trimethyl-pyrrole-3-carboxamide

The process is analogous to that described in Step A of Example 45.

Step B:5-[5-(Aminomethyl)-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl]-N-[4-(benzyloxy)phenyl]-N,1,2-trimethyl-M-pyrrole-3-carboxamidehydrochloride

The compound of Preparation III (1.84 g; 3.99 mmol) and the compound ofStep A (1.60 g; 4.48 mmol) are dissolved in dimethylacetamide (20 mL)and then nitrogen is bubbled through the solution for 5 minutes.Potassium acetate (0.78 g; 7.48 mmol) andbis(triphenylphosphine)palladium(II) dichloride (0.28 g; 0.4 mmol) areadded to the mixture which is then heated to 105° C. and, after stirringfor 10 minutes, water (11 is added. Stirring at 105° C. under a nitrogenatmosphere is continued for 6 hours more. The reaction mixture isallowed to cool to ambient temperature, the resulting mixture isfiltered over a short Celite column and is then purified by preparativeHPLC using water-TFA and acetonitrile as eluants. The pH of theappropriate fractions is adjusted to 7 with NaHCO₃ and then theacetonitrile is evaporated off under reduced pressure. The solidprecipitate is removed by filtration and then dried (5 mbar, 45° C., 16hours) to form tert-butyl[3-(4-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-1,5-dimethyl-1H-pyrrol-2-yl)-4-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}benzyl]carbamatewhich is dissolved/suspended in 4M HCl in dioxane (35 mL). Theheterogeneous mixture is stirred for 30 minutes at ambient temperatureand then evaporated to dryness to yield the title compound which is usedin the next Step without purification.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₉H₄₀N₄O₃

[M+H]⁺ calculated: 613.3180

[M+H]⁺ measured: 613.3194

IR: ν: N—H+: 2854 cm⁻¹; >C═O: 1621 cm⁻¹; C—O—C: 1234, 1120, 1011 cm⁻¹

Step C: Phenyl(3-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-4-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}benzyl)carbamate

The title compound is obtained starting from the compound of the aboveStep in accordance with the process of Step D of Example 45.

Elemental microanalysis: (%, measured(theoretical))

% C=73.2 (72.88); % H=5.83 (5.96); % N=8.13 (8.72).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₉H₃₈N₄O₅

[M+H]⁺ calculated: 643.2922

[M+H]⁺ measured: 643.2902

EXAMPLE 41

N-(3-Fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

Elemental microanalysis: (%, measured(theoretical))

% C=71.44 (71.95); % H=4.95 (5.22); % N=6.8 (6.8).

High-resolution mass spectrometry (ESP):

Empirical formula: C₃₇H₃₃FN₃O₅

[M+H]⁺ calculated: 618.2399

[M+H]⁺ measured: 618.2392

EXAMPLE 42

N-(4-Hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

Elemental microanalysis: (%, measured(theoretical))

% C=71.32 (71.65); % H=5.17 (5.4); % N=10.67 (10.71).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₉H₃₆N₅O₅

[M+H]⁺ calculated: 654.2711

[M+H]⁺ measured: 654.2710

EXAMPLE 43

N-(4-Hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-1H-pyrrole-3-carboxamide

Elemental microanalysis: (%, measured(theoretical))

% C=73.9 (74.11); % H=5.16 (5.55); % N=6.81 (7.01).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₇H₃₄N₃O₅

[M+H]⁺ calculated: 600.2493

[M+H]⁺ measured: 600.2495

EXAMPLE 44

N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]-pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, measured(theoretical)) % C=66.41 (66.62); %H=5.08 (5.59); % N=10.85 (10.84); % Cl−=4.68 (4.57).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₃H₄₂N₆O₆

[M+H]⁺ calculated: 739.3239

[M+H]⁺ measured: 739.3246

EXAMPLE 45

Phenyl[2-(3-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-4-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-phenyl)ethyl]carbamate

Step A: N-(4-Benzyloxyphenyl)-N,1,2-trimethyl-pyrrole-3-carboxamide

To a suspension of 1,2-dimethylpyrrole-3-carboxylic acid (2.085 g; 15mmol) in 1,2-dichloroethane (40 mL) there is added1-chloro-N,N,2-trimethyl-prop-1-en-1-amine (2.37 mL; 17.9 mmol), and thesolution formed is stirred for 1 hour. To the resulting solution thereis added, dropwise, an ice-cold solution of 4-benzyloxy-N-methyl-aniline(3.73 g; 15 mmol) and N-ethyl-N-isopropyl-propan-2-amine (7.75 mL; 45mmol) in 1,2-dichloroethane (40 mL). The reaction mixture is stirred atambient temperature for 1 hour; it is then diluted with dichloromethane(250 mL) and washed with water (2×30 mL), dried over Na₂SO₄ andevaporated. The crude product is triturated with diethyl ether and thesolid formed is filtered off to yield the title compound.

IR: ν: >C═O: 1616 cm⁻¹; amide: 1508 cm⁻¹; C—O—C: 1230, 1172, 1009 cm⁻¹

Step B: tert-Butyl{2-[3-(4-{[4-(benzyloxy)phenyl](methyl)carbamoyl}-1,5-dimethyl-1H-pyrrol-2-yl)-4-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl]ethyl}-carbamate

The compound of Preparation 1 (0.869 g; 1.67 mmol) and the compound ofStep A (0.558 g; 1.67 mmol) are dissolved in dimethylacetamide (8 mL)and then nitrogen is bubbled through the solution for 5 minutes.Potassium acetate (0.33 g; 3.34 mmol) andbis(triphenylphosphine)palladium(II) dichloride (0.117 g; 0.167 mmol)are added to the mixture which is then heated to 140° C. and, afterstirring for 10 minutes, water (80 μL) is added. Stirring at 140° C.under a nitrogen atmosphere is continued for 16 hours more. The reactionmixture is allowed to cool to ambient temperature and then evaporated.The residue is partitioned between dichloromethane (100 mL) and water(20 mL). The organic phase is washed with water (20 mL), dried overNa₂SO₄ and evaporated. The residue was purified by preparative HPLCusing water-TFA and acetonitrile as eluants. The pH of the appropriatefractions is adjusted to 12 using aqueous NaOH solution and then theacetonitrile is evaporated off under reduced pressure. The aqueousresidue is extracted with dichloromethane (2×100 mL). The organic phaseis dried over Na₂SO₄ and evaporated to dryness to yield the titlecompound.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₅H₅₀N₄O₅

[M+H]⁺ calculated: 727.3861

[M+H]⁺ measured: 727.3852

IR: ν: 1705, 1618 cm⁻¹; amide: 1509 cm⁻¹; C—O—C: 1242, 1166, 1012 cm⁻¹

Step C:5-[5-(2-Aminoethyl)-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl]-N-[4-(benzyloxy)phenyl]-N,1,2-trimethyl-1H-pyrrole-3-carboxamidehydrochloride

The compound of Step B (0.35 g; 0.48 mmol) was dissolved/suspended in 4MHCl in dioxane (3 mL). The heterogeneous mixture is stirred for 30minutes at ambient temperature and then evaporated to dryness to yieldthe title compound which is used in next Step without being otherwisepurified.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₄₂N₄O₃

[M+H]⁺ calculated: 627.3337

[M+H]⁺ measured: 627.3309

IR: ν: C—H: 2931 cm⁻¹; >C═O: 1608 cm⁻¹; amide: 1508 cm⁻¹; C—O—C: 1233,1012 cm⁻¹

Step D: Phenyl2-(3-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-4-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)ethyl]-carbamate

The compound of Step C (0.10 g; 0.15 mmol) is dissolved indichloromethane. Phenyl chloroformate (0.027 g; 0.17 mmol) anddiisopropylethylamine (0.097 g, 0.75 mmol) are added thereto. Thereaction mixture is stirred at ambient temperature for 30 minutes. Afterdilution with dichloromethane (100 mL), the organic phase is washed withwater (20 mL), evaporated and concentrated. The residue is thendissolved in ethanol and a Pd/C catalyst is added (10 mg). The reactionmixture is hydrogenated at atmospheric pressure at ambient temperature.When the reaction is complete, the catalyst is removed by filtration,the filtrate is concentrated and the crude product is purified bychromatography over silica gel using dichloromethane and methanol aseluants, to yield the title product.

Elemental microanalysis: (%, measured(theoretical))

% C=72.36 (73.15); % H=6.15 (6.14); % N=8.14 (8.53).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₄₀N₄O₅

[M+H]⁺ calculated: 657.3077

[M+H]⁺ measured: 657.3062

EXAMPLE 46

N-(4-Hydroxyphenyl)-N,1,2-trimethyl-5-(2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-{2-[(phenoxyacetyl)amino]ethyl}phenyl)-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example45 using 2-phenoxyacetyl chloride as acylating agent in Step D.

Elemental microanalysis: (%, measured(theoretical))

% C=72.74 (73.41); % H=6.38 (6.31); % N=7.65 (8.35).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₁H₄₂N₄O₅

[M+H]⁺ calculated: 671.3235

[M+H]⁺ measured: 671.3226

EXAMPLE 47

N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, measured(theoretical))

% C=64.25 (64.59); % H=5.4 (5.7); % N=11.41 (11.59); % Cl−=4.93 (4.89).

EXAMPLE 48

N-(4-Hydroxyphenyl)-N-(2-methoxypyrimidin-5-yl)-1,2-dimethyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

Elemental microanalysis: (%, measured(theoretical))

% C=68.07 (68.45); % H=5(5.27); % N=10.74 (11.09)

EXAMPLE 49

N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamidedihydrochloride

Step A:N-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 11 and(3S)-3-(4-morpholinylmethyl)-1,2,3,4-tetrahydroisoquinoline (seePreparation 3′) in Step A, and the compound of Preparation 11″ in StepC.

Step B:N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamidedihydrochloride

To a solution of 0.21 g (0.2 mmol) of the compound of Step A in 3 mL ofacetic acid there are added 85 mg of sodium cyanoborohydride (5equivalents). The reaction mixture is stirred for 3 hours at ambienttemperature and then overnight at 50° C. There are then added 2.6equivalents of sodium cyanoborohydride and the reaction mixture isheated at 50° C. for 3 hours. The operation is repeated for a secondtime (addition of 2.6 equivalents of sodium cyanoborohydride and thenheating at 50° C. for 3 hours). After coevaporation of the acetic acidin the presence of toluene, the residue is taken up in 3 mL of methanol.The pH of the solution is adjusted to 12 using 1M methanolic potassiumhydroxide solution. After stirring overnight at ambient temperature, thereaction mixture is poured into saturated aqueous sodium bicarbonatesolution and extracted with dichloromethane. The resulting organic phaseis washed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The product obtained is purified by chromatographyover silica gel (dichloromethane/ethanol/ammonia 94/6/0.6) and then overa Lichroprep RP18 column (water/acetonitrile/trifluoroacetic acid).After evaporation of the acetonitrile, the product is neutralised withsodium bicarbonate. It is then extracted with ethyl acetate. The organicphase is dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue obtained is dissolved in acetonitrile andconverted into salt form with 1M aqueous HCl to solution. Afterlyophilisation, the title product is obtained in the form of a solid.

High-resolution muss spectrometry (ESI+):

Empirical formula: C₄₃H₄₄N₆O₆

[M+H]⁺ calculated: 741.3395

[M+H]⁺ measured: 741.3400

EXAMPLE 50

N-(4-Hydroxyphenyl)-N-(2-methoxypyrimidin-5-yl)-1,2-dimethyl-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₄₀N₆O₇

[M+H]⁺ calculated: 717.3031

[M+H]⁺ measured: 717.3031

EXAMPLE 51

5-(5-{[(Benzylcarbamoyl)amino]methyl}-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example40 using benzyl isocyanate as acylating agent in Step C.

Elemental microanalysis: (%, measured(theoretical))

% C=73.39 (73.26); % H=6.16 (6.3); % N=10.08 (10.68).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₄₁N₅O₄

[M+H]⁺ calculated: 656.3239

[M+H]⁺ measured: 656.3226

EXAMPLE 52

5-(5-{[(Ethylcarbamoyl)amino]methyl}-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example40 using ethyl isocyanate as acylating agent in Step C.

Elemental microanalysis: (%, measured(theoretical))

% C=71.4 (70.8); % H=6.41 (6.62); % N=11.24 (11.8).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₅H₃₉N₅O₄

[M+H]⁺ calculated: 594.3082

[M+H]⁺ measured: 594.3069

EXAMPLE 53

N-(4-Hydroxyphenyl)-N,1,2-trimethyl-5-(2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-{[(phenoxyacetyl)amino]methyl}phenyl)-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example40 using 2-phenoxyacetyl chloride as acylating agent in Step C.

Elemental microanalysis: (%, measured(theoretical))

% C=72.32 (73.15); % H=6.21 (6.14); % N=7.84 (8.53).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₄₀N₄O₅

[M+H]⁺ calculated: 657.3079

[M+H]⁺ measured: 657.3105

EXAMPLE 54

N-(4-Hydroxyphenyl)-1,2-dimethyl-5-(2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-{[(phenoxyacetyl)amino]methyl}phenyl)-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

Elemental microanalysis: (%, measured(theoretical)

% C=73.87 (73.04); % H=5.47 (5.74); % N=10.26 (10.87)

EXAMPLE 55

5-(5-[2-({[2-(4-Fluorophenyl)ethyl]sulphonyl}amino)ethyl]-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example45 using 2-(4-fluorophenyl)ethanesulphonyl chloride as acylating agentin Step D.

Elemental microanalysis: (%, measured(theoretical))

% C=67.42 (68.12); % H=5.76 (6); % N=7.27 (7.75); S=3.68 (4.44).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₁H₄₃FN₄O₅S

[M+H]⁺ calculated: 723.3018

[M+H]⁺ measured: 723.3011

EXAMPLE 56

5-(5-{2-[(Benzylcarbamoyl)amino]ethyl}-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example45 using benzyl isocyanate as acylating agent in Step D.

Elemental microanalysis: (%, measured(theoretical))

% C=71.14 (73.52); % H=6.47 (6.47); % N=9.42 (10.46).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₁H₄₃N₅O₄

[M+H]⁺ calculated: 670.3395

[M+H]⁺ measured: 670.3390

EXAMPLE 57

N-(4-Hydroxyphenyl)-N,1,2-trimethyl-5-(2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-{2-[(phenylacetyl)amino]ethyl}phenyl)-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example45 using phenylacetyl chloride as acylating agent in Step D.

Elemental microanalysis: (%, measured(theoretical))

% C=75.46 (75.21); % H=6.11 (6.46); % N=8.31 (8.56).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₁H₄₂N₄O₄

[M+H]⁺ calculated: 655.3286

[M+H]⁺ measured: 655.3285

EXAMPLE 58

N-(4-Hydroxyphenyl)-N,1,2-trimethyl-5-(2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-{2-[(phenylcarbamoyl)amino]ethyl}phenyl)-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example45 using phenyl isocyanate as acylating agent in Step D.

Elemental microanalysis: (%, measured(theoretical))

% C=71.25 (73.26); % H=6.12 (6.3); % N=9.61 (10.68).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₄₁N₅O₄

[M+H]⁺ calculated: 656.3239

[M+H]⁺ measured: 656.3226

EXAMPLE 59

5-(4-[({[2-(4-Fluorophenyl)ethyl]sulphonyl}amino)methyl]-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example32 using 2-(4-fluorophenyl)ethanesulphonyl chloride as sulphonylationagent in Step D.

Elemental microanalysis: (%, measured(theoretical))

% H=5.19 (5.83); % N=7.28 (7.9); S=4.45 (4.52); % C=66.17 (67.78).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₄₁FN₄O₅S

[M+H]⁺ calculated: 709.2866

[M+H]⁺ measured: 709.2866

EXAMPLE 60

5-(5-Chloro-2-{[(3S)-3-{[2-(dimethylamino)ethoxy]methyl}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-phenyl-1H-pyrrole-3-carboxamide hydrochloride

The process of Example 29 is used, on the one hand replacing the4-(2-bromoethyl)morpholine hydrobromide used in Step B by2-chloroethyldimethylamine hydrochloride and on the other hand adding acatalytic amount of tetrabutylammonium iodide.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₄₁ClN₄O₄

[M+H]⁺ calculated: 677.2890

[M+H]⁺ measured: 677.2887

EXAMPLE 61

N-(4-Hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(pyridin-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₆H₃₂N₄O₅

[M+H]⁺ calculated: 601.2445

[M+H]⁺ measured: 601.2424

EXAMPLE 62

5-(5-Fluoro-4-methoxy-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

Elemental microanalysis: (%, measured(theoretical))

% C=68.99 (69.18); % H=5.89 (5.64); % N=11.35 (11.52).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₅H₃₄FN₅O₄

[M+H]⁺ calculated: 608.2668

[M+H]⁺ measured: 608.2640

EXAMPLE 63

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]-pyridin-5-yl)-1H-pyrrole-3-carboxamide

Elemental microanalysis: (%, measured(theoretical))

% C=70.48 (70.85); % H=5.67 (5.32); % N=11.2 (10.87).

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₈H₃₄ClN₅O₃

[M+H]⁺ calculated: 666.2242

[M+H]⁺ measured: 666.2235

EXAMPLE 64

N,1,2-Trimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₈H₄₀N₆O₅

[M+H]⁺ calculated: 661.3133

[M+H]⁺ measured: 661.3125

EXAMPLE 65

1,2-Dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-1H-pyrrole-3-carboxamidehydrochloride

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₃H₄₂N₆O₅

[M+H]⁺ calculated: 723.3289

[M+H]⁺ measured: 723.3287

EXAMPLE 66

4-Methylphenyl(4-{4-[(4-hydroxyphenyl)(methyl)carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-3-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}benzyl)carbamate

The title compound is obtained in accordance with the process of Example32 using 4-methylphenyl chloroformate as acylating agent in Step D.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₄₀N₄O₅

[M+H]⁺ calculated: 657.3079

[M+H]⁺ measured: 657.3076

EXAMPLE 67

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, measured(theoretical))

% C=65.69 (65.28); % H=5.38 (5.77); % N=11.18 (12.02); % Cl−=5.61 (5.07)

EXAMPLE 68

5-(5-Fluoro-4-hydroxy-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

A 1N solution of tribromoborane (1.3 equivalents) in dichloromethane ispoured rapidly, at ambient temperature, into a solution of the compoundof Example 62 in dichloromethane. This operation is repeated twice inorder to complete the reaction in 5 hours. The reaction mixture ispoured into anhydrous ethanol at 5° C. After stirring for 10 minutes,saturated aqueous NaHCO₃ solution is added. The mixture is extractedwith dichloromethane, dried over Na₂SO₄ and concentrated to dryness. Thecrude product obtained is purified by preparative HPLC using water, TFAand acetonitrile as eluants. The pH of the appropriate fractions isadjusted to 12 with saturated aqueous NaHCO₃ solution, and then theacetonitrile is evaporated off under reduced pressure. The aqueousresidue is extracted with dichloromethane. The organic phase is driedover Na₂SO₄ and evaporated to dryness to yield the title compound.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₄H₃₂FN₅O₄

[M+H]⁺ calculated: 594.2511

[M+H]⁺ measured: 594.2517

EXAMPLE 69

N-(4-Hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3S)-3-[(4-methylpiperazin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₄H₄₅N₇O₅

[M+H]⁺ calculated: 752.3555

[M+H]⁺ measured: 752.3552

EXAMPLE 70

N-(4-Hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3S)-3-[(4-methylpiperazin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(pyridin-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₁H₄₂N₆O₅

[M+H]⁺ calculated: 699.3289

[M+H]⁺ measured: 699.3293

EXAMPLE 71

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₂H₄₁ClN₆O₄

[M+H]⁺ calculated: 723.3289

[M+H]⁺ measured: 723.3287

EXAMPLE 72

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-benzimidazol-5-yl)-1H-pyrrole-3-carboxamide

Elemental microanalysis: (%, measured(theoretical))

% C=68.90 (69.17); % H=5.32 (5.67); % N=11.40 (11.52).

EXAMPLE 73

N-(4-Hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(pyridin-4-yl)-1H-pyrrole-3-carboxamidedihydrochloride

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₃₉N₅O₆

[M+H]⁺ calculated: 686.2973

[M+H]⁺ measured: 686.2971

EXAMPLE 74

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(pyridin-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₉H₃₈ClN₅O₄

[M+H]⁺ calculated: 676.2685

[M+H]⁺ measured: 676.2684

EXAMPLE 75

N-(4-Hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=60.12:59.77: % H=4.92:4.76; % N=10.79:10.39% Cl−=4.55:5.17.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₉H₃₇F₃N₆O₆

[M+H]⁺ calculated: 743.2799

[M+H]⁺ measured: 742.2802

EXAMPLE 76

2-(Difluoromethyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 77

N-(4-Hydroxyphenyl)-2-(methoxymethyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 78

2-(2,2-Difluoroethyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 79

N-(4-Hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-2-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 80

N-(4-Hydroxyphenyl)-2-(2-methoxyethyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 81

N-(4-Hydroxyphenyl)-1-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)-2-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-3-carboxamidehydrochloride

The procedure is in accordance with the general protocol of Example 1using the compound of Preparation 22 in Step A. The product obtained isfinally dissolved in acetonitrile and converted into salt form using0.1M aqueous HCl solution. After a lyophilisation step, the expectedcompound is obtained in the form of a solid.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₄₂N₆O₆

[M+H]⁺ calculated: 703.3239

[M+H]⁺ measured: 703.3236

EXAMPLE 82

N-(4-Hydroxyphenyl)-1-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)-2-(morpholin-4-ylmethyl)-1H-pyrrole-3-carboxamide

The procedure is in accordance with the general protocol of Example 1using the compound of Preparation 23 in Step A.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₉H₄₀N₆O₆

[M+H]⁺ calculated: 689.3082

[M+H]⁺ measured: 689.3085

EXAMPLE 83

N-(4-Hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 84

2-(Difluoromethyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 85

N-(4-Hydroxyphenyl)-2-(methoxymethyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 86

2-(2,2-Difluoroethyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 87

N-(4-Hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-2-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 88

N-(4-Hydroxyphenyl)-2-(2-methoxyethyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

The procedure is in accordance with the general protocol of Example 1using the appropriate Preparations. The product obtained is finallydissolved in acetonitrile and converted into salt form using 0.1Maqueous HCL solution. After a lyophilisation step, the expected compoundis obtained in the form of a solid.

Elemental microanalysis: (%, theoretical:measured)

% C=65.97:66.15; % H=5.78:5.46; % N=10.26:10.24; % Cl−=4.33:4.76.

High-resolution Mass spectrometry (ESI/FIA/HR and MS/MS):

Empirical formula: C₄₅H₄₆N₆O₇

[M+H]⁺ calculated: 783.3501

[M+H]⁺ measured: 783.3502

EXAMPLE 89

N-(4-Hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-[2-(morpholin-4-yl)ethyl]-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 90

N-(4-Hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(morpholin-4-ylmethyl)-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 91

N-(4-Hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 92

1-Ethyl-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

The procedure is in accordance with the protocol described in Example 1,using the compounds from Preparations 20 and 3′ in Step A and thecompound from Preparation 1″ in Step C. The product obtained is finallydissolved in acetonitrile and converted into salt form using 0.1Maqueous HCl solution. After a lyophilisation step, the expected compoundis obtained in the form of a solid.

Elemental microanalysis: (%, theoretical:measured)

% C=64.99:65.61; % H=5.86:5.39; % N=11.37:11.43; % Cl=4.80:4.42.

[M+H]⁺ measured: 703.3236

EXAMPLE 93

N-(4-Hydroxyphenyl)-1-(2-methoxyethyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=64.01:64.10; % H=5.90:5.63; % N=10.92:10.88; % Cl−=4.61:4.70.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₁H₄₄N₆O₇

[M+H]⁺ calculated: 733.3344

[M+H]⁺ measured: 733.3345

EXAMPLE 94

1-(2-Fluoroethyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

The procedure is in accordance with the protocol described in Steps A-Dof Example 1, using the compounds from Preparations 21 and 3′ in Step Aand the compound from Preparation 1″ in Step C. The product obtained isfinally dissolved in acetonitrile and converted into salt form using0.1M aqueous HCl solution. After a lyophilisation step, the expectedcompound is obtained in the form of a solid.

Elemental microanalysis: (%, theoretical:measured)

% C=63.44:63.25; % H=5.59:5.09; % N=11.10:11.02; % Cl=4.68:4.74.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₄₁FN₆O₆

[M+H]⁺ calculated: 721.3144

[M+H]⁺ measured: 721.3147

EXAMPLE 95

1-(2,2-Difluoroethyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 32 and the compound of Preparation 3′ inStep A, and the compound of Preparation 1″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=61.97:61.89; % H=5.33:5.04; % N=10.84:10.85: % Cl=4.57:4.55

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₄₀H₄₀F₂N₆O₆

[M+H]⁺ calculated: 739.3050

[M+H]⁺ measured: 739.3052

EXAMPLE 96

N-(4-Hydroxyphenyl)-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)-1-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-3-carboxamidehydrochloride

Step A:N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-2-methyl-5-[6-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,3-benzodioxol-5-yl]-N-(1-methyl-1H-pyrazol-4-yl)-1-(2-morpholinoethyl)pyrrole-3-carboxamide

The compound obtained in Step E of Example 99 is dissolved in 6 mL oftetrahydrofuran.

Sodium iodide (100 mg, 0.67 mmol) is added, followed by morpholine (0.21mL, 2.53 mmol) dropwise. The reaction mixture is heated in a sealedflask at 90° C. for 72 hours. After cooling, the solution is evaporatedto dryness and the residue is purified by chromatography over silica gelusing dichloromethane and methanol as eluants. The expected product isobtained in the form of a foam.

¹H NMR (500 MHz, dmso-d6) δ ppm: 7.7-7.45 (4 bs, 1H), 7.2-6.9 (m, 4H),7.1-6.4 (m, 2H), 7.1-6.9 (4 bs, 1H), 7-6.8 (4 m, 2H), 6.75/6.48 (d+bs,2H), 6.1 (4 bs, 2H), 5.25-4.7 (4 bs, 1H), 5.2-3.8 (m, 2H), 4.9/4.65/3.8(3 m, 1H), 3.75 (4 s, 3H), 3.5 (bs, 4H), 3-2 (m, 10H), 2.41/2.3 (2 bs,3H), 1.02/0.95/0.78 (3 bd, 3H), 0.88 (m, 9H), 0.1 (m, 6H)

IR (ATR) cm⁻¹: 1626 δ>C═O amides

Step B:N-(4-Hydroxyphenyl)-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)-1-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-3-carboxamidehydrochloride

The procedure is in accordance with the protocol described in Step D ofExample 1. The product obtained is finally subjected to a step ofconversion into salt form in the presence of HCl in ether. Afterfiltration and lyophilisation in a mixture of acetonitrile/water, the toexpected compound is obtained.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₄₂N₆O₆

[M+H]⁺ calculated: 703.3239

[M+H]⁺ measured: 703.3238

EXAMPLE 97

N-(4-Hydroxyphenyl)-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-[2-(morpholin-4-yl)ethyl]-N-phenyl-1H-pyrrole-3-carboxamidehydrochloride

The procedure is in accordance with the protocol described in Example 96replacing the compound of Preparation 1″ by that of Preparation 2″.

Elemental microanalysis: (%, theoretical:measured)

% C=68.61:68.12; % H=5.89:5.23; % N=7.62:7.54; % Cl−=4.82:4.66.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS):

Empirical formula: C₄₂H₄₂N₄O₆

[M+H]⁺ calculated: 699.3177

[M+H]⁺ measured: 699.3173

EXAMPLE 98

1-[2-(Dimethylamino)ethyl]-N-(4-hydroxyphenyl)-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-1H-pyrrole-3-carboxamidehydrochloride

The procedure is in accordance with the protocol described in Example 27replacing the compound of Preparation 1″ by that of Preparation 2″. Theproduct obtained is finally subjected to a step of conversion into saltform in the presence of 1M HCl in ether. After filtration andlyophilisation in a mixture of acetonitrile/water, the expected compoundis obtained.

Elemental microanalysis: (%, theoretical:measured)

% C=69.30:69.20; % H=5.96:5.48; % N=8.08:8.08; % Cl−=5.11:5.03.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS):

Empirical formula: C₄₀H₄₀N₄O₅

[M+H]⁺ calculated: 657.3071

[M+H]⁺ measured: 657.3066

EXAMPLE 99

N-(4-Hydroxyphenyl)-1-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

Step A: Ethyl1-(2-benzyloxyethyl)-2-methyl-5-[6-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,3-benzodioxol-5-yl]pyrrole-3-carboxylate

The procedure is in accordance with the protocol described in Step A ofExample 1 replacing the compound of Preparation 1 by that of Preparation19.

¹H NMR (500 MHz, dmso-d6) δ ppm: 7.35-6.95 (m, 9H), 7-6.8 (several s,2H), 6.35-5.85 (several s, 1H), 6.15 (several s, 2H), 5.15-3.5 (severalm, 4H), 4.9/4.7/3.95 (several m, 1H), 4.4 (m, 2H), 4.2-3.95 (m, 2H),3.55 (m, 2H), 3.1-2.35 (several m, 2H), 2.5-2.2 (several s, 3H),1.25-1.1 (several m, 3H), 1.05-0.7 (several d, 3H)

Step B:1-(2-Benzyloxyethyl)-2-methyl-5-[6-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,3-benzodioxol-5-yl]pyrrole-3-carboxylicAcid

The procedure is in accordance with the protocol described in Step B ofExample 1.

IR (ATR) cm⁻¹: 3000-2500 ν —OH, 1675-1625 ν —C═O carboxylic acid+amide

Step C:1-(2-Benzyloxyethyl)-N-[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-2-methyl-5-[6-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,3-benzodioxol-5-yl]-N-(1-methyl-1H-pyrazol-4-yl)pyrrole-3-carboxamide

The procedure is in accordance with the protocol described in Step C ofExample 1.

¹H NMR (500 MHz, dmso-d6) δ ppm: 7.7-7.5 (several s, 1H), 7.35-6.5(several m, 11H), 7.1-6.9 (several s, 1H), 6.95-6.5 (several s, 2H),6.8/6.5 (m, 2H), 6.05 (several s, 2H), 5.25-4.7 (several s, 1H), 5.1-3.6(several m, 4H), 4.85/4.6/3.75 (several in, 1H), 4.3 (m, 2H), 3.7 (2×s,3H), 3.4 (m, 2H), 3.05-2.4 (several m, 2H), 2.4-2.25 (several s, 3H),1-0.75 (several d, 3H), 0.9 (several s, 9H), 0.1 (several s, 6H)

IR (ATR) cm⁻¹: 1629 ν>C═O amides

Step D:N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-1-(2-hydroxyethyl)-2-methyl-5-[6-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,3-benzodioxol-5-yl]-N-(1-methyl-1H-pyrazol-4-yl)pyrrole-3-carboxamide

In a hydrogenating reactor, the compound of the above Step is dissolvedin 30 mL of methanol. The solution is degassed by bubbling argon in, andpalladium-on-carbon 10% (550 mg) is added. The resulting suspension isstirred under a pressure of 1 bar of hydrogen for 15 hours, and thenpassed through a Whatman® filter. The catalyst is rinsed with methanoland the filtrate is evaporated in vacuo. The residue thereby obtained ispurified by chromatography over silica gel using dichloromethane andmethanol as eluants. The expected product is obtained in the form of anoil.

¹H NMR (500 MHz, pyridine-d5) δ ppm: 7.7-7.4 (4 s, 1H), 7.3-6.9 (m, 4H),7.1-6.8 (4 s, 1H), 7-6.7 (m, 2H), 6.9-6.4 (m, 2H), 6.8-6.4 (4 m, 2H),6.1 (m, 2H), 5.2/5/4.7 (4 s, 1H), 5.15-3.9 (8 d, 2H), 4.9-4.8 (m, 1H),4.9/4.7/3.85 (3 in, 1H), 3.9-3.7 (m, 2H), 3.75 (2 s, 3H), 3.5-3.2 (m,2H), 3-2.4 (m, 2H), 2.4-2.3 (4 s, 3H), 1.05/0.95/0.75 (4 d, 3H), 0.85(bs, 9H), 0.15-0 (in, 6H)

IR (ATR) cm⁻¹:3346 ν —OH primary alcohol, 1621 ν —C═O amides

Step E:2-[3-[[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-(1-methyl-1H-pyrazol-4-yl)-carbamoyl]-2-methyl-5-[6-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,3-benzodioxol-5-yl]pyrrol-1-yl]ethylmethanesulphonate

The compound of the above Step (2.37 g, 3.17 mmol) is dissolved in 30 mLof tetrahydrofuran. The reaction mixture is cooled to 0° C. and thereare successively added triethylamine (1.8 mL, 13.9 mmol) and, dropwise,methanesulphonyl chloride (0.40 mL, 5.17 mmol). The reaction mixture isstirred for 2 hours at 0° C. The reaction mixture is then poured intosaturated aqueous sodium hydrogen carbonate solution and extracted 3times with ethyl acetate. The organic phase is washed 3 times withbrine, dried over MgSO₄, filtered and then evaporated to dryness. Theevaporation residue is used without purification in the next Step.

¹H NMR (500 MHz, dmso-d6) δ ppm: 7.7-7.45 (several s, 1H), 7.25-6.4 (m,8H), 7.1-6.9 (several s, 1H), 6.95-6.65 (several s, 2H), 6.1 (several s,2H), 5.2-4.6 (several s, 1H), 5.05-3.75 (several d, 2H), 4.9/4.6/3.9/3.8(several m, 1H), 4.3-4.05 (m, 2H), 4.2-3.95 (m, 2H), 3.75/3.7 (2 s, 3H),3.05-2.5 (several m, 2H), 3 (several s, 3H), 2.45-2.3 (several s, 3H),1.05-0.75 (several d, 3H), 0.9 (several s, 9H), 0.1 (several s, 6H)

IR (ATR) cm⁻¹: 1626 ν —C═O, 1349 ν —SO₂, 1249 δ —CH3, 1172 ν —SO₂

Step F:N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-1-[2-[2-methoxyethyl(methyl)amino]-ethyl]-2-methyl-5-[6-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,3-benzodioxol-5-yl]-N-(1-methyl-1H-pyrazol-4-yl)pyrrole-3-carboxamide

The compound of the above Step (1.33 mg, 1.61 mmol) is dissolved in 6 mLof tetrahydrofuran. Sodium iodide (100 mg, 0.67 mmol) is added, followedby dimethylamine (0.172 g, 1.932 mmol) dropwise. The reaction mixture isheated in a sealed flask at 60° C. for 36 hours. After cooling, it isevaporated to dryness and purified by chromatography over silica gelusing dichloromethane and ammonia-in-methanol as eluants. The expectedproduct is obtained in the form of a foam.

¹H NMR (500 MHz, dmso-d6) δ ppm 7.7-7.45 (4 bs, 1H), 7.2-6.9 (m, 4H),7.1-6.9 (4 bs, 1H), 7-6.7 (4 m, 2H), 7/6.45 (2 m, 2H), 6.8/6.45 (2 in,2H), 6.1 (m, 2H), 5.22/5.05/4.7 (4 bs, 1H), 5.2-3.8 (m, 2H),4.91/4.65/3.9 (3 m, 1H), 3.75 (2 bs, 3H), 3.7 (m, 2H), 3.2 (bs, 3H), 3-2(m, 2H), 2.7-2 (ml, 6H), 2.7-2 (m, 3H), 2.45/2.35 (2 bs, 3 II),1.05/0.95/0.8 (3 bd, 3H), 0.9 (m, 9H), 0.1 (m, 6H)

IR (ATR) cm⁻¹: 1628 (shoulder) δ —C═O amides

Step G:N-(4-hydroxyphenyl)-1-[2-[2-methoxyethyl(methyl)amino]ethyl]-2-methyl-5-[6-[(3R)-3-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,3-benzodioxol-5-yl]-N-(1-methyl-1H-pyrazol-4-yl)pyrrole-3-carboxamidehydrochloride

The procedure is in accordance with the protocol described in Step D ofExample 1. The product obtained is finally subjected to a step ofconversion into salt form in the presence of 1M HCl in ether. Afterfiltration and lyophilisation in a mixture of acetonitrile/water, theexpected compound is obtained.

IR (ATR) cm⁻¹: 2000 to 3500 ν —NH⁺/OH, 1615 ν>C═O amides, 1237-1161δ>C—O—C<, 745 ν>CH—Ar.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₄₄N₆O₆

[M+H]⁺ calculated: 705.3395

[M+H]⁺ measured: 705.3391

EXAMPLE 100

5-(5-Fluoro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

The procedure is in accordance with the general protocol of Example 1using the appropriate Preparations. The product obtained is finallydissolved in acetonitrile and converted into salt form using 0.1Maqueous HCl solution. After a lyophilisation step, the expected compoundis obtained in the form of a solid.

Elemental microanalysis: (%, theoretical:measured)

% C=64.23:64.31; % H=5.80:5.43; % N=11.52:11.46; % Cl−=4.86:4.95.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₉H₄₁FN₆O₅

[M+H]⁺ calculated: 693.3195

[M+H]⁺ measured: 693.3194

EXAMPLE 101

5-(4-Fluoro-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 27 and the compound of Preparation 3′ inStep A, and the compound of Preparation 1″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical: measured)

% C=64.23:63.12; % H=5.80:5.20; % N=11.52:11.38. % Cl=4.86:5.03.

High-resolution mass spectrometry (ESI+/HR, ESI−/IR):

Empirical formula: C₃₉H₄₁FN₆O₅

[M+H]⁺ calculated: 693.3195

[M+H]⁺ measured: 693.3195

EXAMPLE 102

5-(5-Chloro-2-{[(3S)-3-[(4-methylpiperazin-1-yl)methyl]-3,4-dihydro-isoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamidetrihydrochloride

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₃H₄₄ClN₇O₃

[M+H]⁺ calculated: 742.3267

[M+H]⁺ measured: 742.3268

EXAMPLE 103

5-(5-Chloro-2-{[(3S)-3-[(4-methylpiperazin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-phenyl-1H-pyrrole-3-carboxamide

EXAMPLE 104

N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolo[3,4-b]-pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 105

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 106

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-phenyl-1H-pyrrole-3-carboxamide

The procedure is in accordance with the general protocol of Example 1using the appropriate Preparations, it being understood that Step D isnot carried out. The expected product is obtained in free base form.

Elemental microanalysis: (%, theoretical:measured)

% C=70.72:69.77; % H=5.79:5.96; % N=11.78:11.43.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₇H₄₁ClN₆O₃

[M+H]⁺ calculated: 713.3001

[M+H]⁺ measured: 713.2998

EXAMPLE 107

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-fluorophenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-11f-pyrrole-3-carboxamide

EXAMPLE 108

5-(5-Chloro-2-{[(3.8)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1-methyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and(3S)-3-(4-morpholinylmethyl)-1,2,3,4-tetrahydroisoquinoline (seePreparation 3′) in Step A, and the compound of Preparation 19″ in StepC. The product obtained is finally subjected to a step of conversioninto salt form in the presence of HCl in ether. After filtration andlyophilisation in a mixture of acetonitrile/water, the expected compoundis obtained.

Elemental microanalysis: (%, theoretical:measured)

% C=64.95:65.09; % H=5.45:5.20; % N=11.36:11.26: % Cl−=4.79:4.62.

High-resolution mass spectrometry (ESI/+):

Empirical formula: C₄₀H₃₉ClN₆O₄

[M+H]⁺ calculated: 703.2794

[M+H]⁺ measured: 703.2789

EXAMPLE 109

5-(5-Chloro-2-{[(1S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(6-cyanopyridin-2-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the compound of Preparation 23″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

High-resolution mass spectrometry (ESI+−/FIA/HR, ESI−/FIA):

Empirical formula: C₄₀H₃₇ClN₆O₄

[M+H]⁺ calculated: 701.2638

[M+H]⁺ measured: 701.2639

EXAMPLE 110

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-cyanopyridin-2-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=65.13:65.72; %11=5.19:4.76; % N=11.39:12.04; % Cl=4.81:4.45.

High-resolution mass spectrometry (ESI+−/FIA/HR, ESI−/FIA):

Empirical formula: C₄₀H₃₇ClN₆O₄

[M+H]⁺ calculated: 701.2638

[M+H]⁺ measured: 701.2643

EXAMPLE 111

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-cyanopyrimidin-2-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide

EXAMPLE 112

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-[2-(dimethylamino)pyridin-4-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide

EXAMPLE 113

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-benzimidazol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 114

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(pyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 115

5-(5-Chloro-2-{[(3S)-3-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamidedihydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 7′ inStep A, and the compound of Preparation 1″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=61.01:60.17; % H=5.74:5.09; % N=12.15:12.02; % Cl=8.78:9.81.

High-resolution mass spectrometry (ESI+−/FIA/HR, ESI−/FIA):

Empirical formula: C₄₁H₄₄ClN₇O₄

[M+H]⁺ calculated: 734.3216

[M+H]⁺ measured: 734.3220

EXAMPLE 116

5-(5-Chloro-2-{[(3S)-3-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamidedihydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 9′ inStep A, and the compound of Preparation 1″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=61.01:61.90; % H=5.74:5.65; % N=12.15:12.14; % Cl=13.15:11.51.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS):

Empirical formula: C₄₁H₄₄ClN₇O₄

[M+H]⁺ calculated: 734.3216

[M+H]⁺ measured: 734.3218

EXAMPLE 117

5-(5-Chloro-2-{[(3S)-3-(fluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 118

5-(5-Chloro-2-{[(3S)-3-(difluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 119

5-(5-Chloro-2-{[(3S)-3-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 120

5-(5-Chloro-2-{[(3S)-3-[(3-cyanoazetidin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 121

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(1-ethyl-1H-pyrazol-4-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide

EXAMPLE 122

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(1-cyclopropyl-1H-pyrazol-4-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the compound of Preparation 28″ in Step C.

Elemental microanalysis: (%, theoretical:measured)

% C=68.12:67,94; % H=5.86:5.77; % N=11.92:11.65.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₄₀H₄₁ClN₆O₄

[M+H]⁺ calculated: 705.2951

[M+H]⁺ measured: 705.2952

EXAMPLE 123

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrrole-3-carboxamide

EXAMPLE 124

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide

EXAMPLE 125

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-1,2-dimethyl-1H-pyrrole-3-carboxamide

EXAMPLE 126

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the compound of Preparation 26″ in Step C.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₄₀H₄₁ClN₆O₅

[M+H]⁺ calculated: 721.2900

[M+H]⁺ measured: 721.2902

EXAMPLE 127

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl]-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the compound of Preparation 22″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=63.81:63.63; % H=5.75:5.74; % N=10.89:10.71; % Cl.=4.59:4.52.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₄₁H₄₃ClN₆O₅

[M+H]⁺ calculated: 735.3056

[M+H]⁺ measured: 735.3061

EXAMPLE 128

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide

EXAMPLE 129

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]-pyridin-5-yl)-N-phenyl-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process describedin Step B of Example 49 using Example 106 as starting material, it beingunderstood that the product is not subjected to the step of conversioninto salt form.

Elemental microanalysis: (%, theoretical:measured)

% C=70.53:70.51; % H=6.06:5.81; % N=11.75:11.71.

High-resolution mass spectrometry (ESI+−/FIA):

Empirical formula: C₄₂H₄₃ClN₆O₃

[M+H]⁺ calculated: 715.3158

[M+H]⁺ measured: 715.3159

EXAMPLE 130

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-fluorophenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 131

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl-1H-pyrrole-3-carboxamide

EXAMPLE 132

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-hydroxypyrimidin-5-yl)-1,2-dimethyl-N-phenyl-1H-pyrrole-3-carboxamide

EXAMPLE 133

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-hydroxypyrimidin-5-yl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 134

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-hydroxypyrimidin-5-yl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 135

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-hydroxypyrimidin-5-yl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 136

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 137

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 138

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 139

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 140

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 141

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 142

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1-ethyl-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 143

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1M-yl]carbonyl}phenyl)-1-ethyl-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 144

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1-ethyl-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 145

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-(2-methoxyethyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 146

5-(5-Chloro-2-{[(18)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-(2-methoxyethyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 147

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-(2-methoxyethyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 148

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1-(2-fluoroethyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 149

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1-(2-fluoroethyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 150

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1-(2-fluoroethyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 151

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1-(2,2-difluoroethyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 152

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1-(2,2-difluoroethyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 153

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1-(2,2-difluoroethyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 154

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 155

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 156

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 157

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-3-carboxamide

EXAMPLE 158

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-3-carboxamide

EXAMPLE 159

5-(5-Chloro-2-{[(3S)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-3-carboxamide

EXAMPLE 160

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-1-[2-(morpholin-4-yl)ethyl]-N-phenyl-1H-pyrrole-3-carboxamide

EXAMPLE 161

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1-[2-(dimethylamino)ethyl]-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 162

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1-[2-(dimethylamino)ethyl]-N-(4-hydroxyphenyl)-2-methyl-N-phenyl-1H-pyrrole-3-carboxamide

EXAMPLE 163

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1-[2-(dimethylamino)ethyl]-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 164

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1-[2-(dimethylamino)ethyl]-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 165

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 166

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 167

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 168

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 169

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 170

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 171

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-2-(difluoromethyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 172

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-2-(difluoromethyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 173

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-2-(difluoromethyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 174

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-(methoxymethyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 175

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-(methoxymethyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 176

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-(methoxymethyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 177

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-2-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 178

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 179

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 180

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-2-(2,2-difluoroethyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 181

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-2-(2,2-difluoroethyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 182

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-2-(2,2-difluoroethyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 183

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-(2-methoxyethyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 184

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-(2-methoxyethyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 185

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-(2-methoxyethyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 186

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-2-(morpholin-4-ylmethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 187

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(morpholin-4-ylmethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 188

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(morpholin-4-ylmethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 189

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-2-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-3-carboxamide

EXAMPLE 190

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-3-carboxamide

EXAMPLE 191

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-3-carboxamide

EXAMPLE 192

5-(5-Chloro-2-{[(3S)-3-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 193

5-(5-Chloro-2-{[(3S)-3-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 194

5-(5-Chloro-2-{[(3S)-3-(difluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 195

5-(5-Chloro-2-{[(3S)-3-(difluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 196

5-(5-Chloro-2-{[(3S)-3-(fluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 197

5-(5-Chloro-2-{[(3S)-3-(fluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 198

5-(5-Chloro-2-{[(3S)-3-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 199

5-(5-Chloro-2-{[(3S)-3-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 200

5-(5-Chloro-2-{[(3S)-3-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 201

5-(5-Chloro-2-{[(3S)-3-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 202

5-(2-{[(3S)-3-(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-chlorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 203

5-(2-{[(3S)-3-(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-chlorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 204

5-(2-{[(3S)-3-(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-chlorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 205

5-(5-Chloro-2-{[(3S)-3-[(3-cyanoazetidin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 206

5-(5-Chloro-2-{[(3S)-3-[(3-cyanoazetidin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 207

5-(5-Chloro-2-{[(3S)-3-(1-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 8′ inStep A, and the compound of Preparation 1″ in Step C.

High-resolution mass spectrometry (ESI+−/FIA/HR, ESI−/FIA):

Empirical formula: C₃₉H₃₉ClN₆O₄

[M+H]⁺ calculated: 691.2794

[M+H]⁺ measured: 691.2796

EXAMPLE 208

5-(5-Chloro-2-{[(3S)-3-(1-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 209

5-(5-Fluoro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

The procedure is in accordance with the general protocol of Example 1using the appropriate Preparations. The product obtained is finallydissolved in acetonitrile and converted into salt form using 0.1Maqueous HCl solution. After a lyophilisation step, the expected compoundis obtained in the form of a solid.

Elemental microanalysis: (%, theoretical:measured)

% C=66.27:66.84; % H=5.69:5.15; % N=10.78:10.71; % Cl−=4.55:4.46.

High-resolution mass spectrometry (ESI+−/FIA):

Empirical formula: C₄₃H₄₃FN₆O₅

[M+H]⁺ calculated: 743.3352

[M+H]⁺ measured: 743.3353

EXAMPLE 210

5-(5-Fluoro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

Step A:5-(5-Fluoro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example1 using the compound of Preparation 14 and(3S)-3-(4-morpholinylmethyl)-1,2,3,4-tetrahydroisoquinoline (seePreparation 3′) in Step A, and the compound of Preparation 11″ in StepC.

Step B:5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-phenyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process describedin Step B of Example 49 starting from compound of the above Step, itbeing understood that the product is finally subjected to a step ofconversion into salt form in the presence of 1M HCl in ether. Afterfiltration and lyophilisation in a mixture of acetonitrile/water, theexpected product is obtained.

Elemental microanalysis: (%, theoretical:measured)

% C=60.12:59.77; % H=4.92:4.76; % N=10.79:10.39; % Cl−=4.55:5.17.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS):

Empirical formula: C₄₀H₄₀N₄O₅

[M+H]⁺ calculated: 657.3071

[M+H]⁺ measured: 657.3066

EXAMPLE 211

5-(4-Fluoro-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 212

5-(4-Fluoro-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 213

N-(1-Ethyl-1H-pyrazol-4-yl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide

EXAMPLE 214

N-(1-Cyclopropyl-1H-pyrazol-4-yl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 8 and the compound of Preparation 3′ inStep A, and the compound of Preparation 28″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=66.24:66.53; % H=5.84:5.39; % N=10.59:10.92% Cl.=4.89:5.68

EXAMPLE 215

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrrole-3-carboxamide

EXAMPLE 216

N-[1-(Difluoromethyl)-1H-pyrazol-4-yl]-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide

EXAMPLE 217

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-1,2-dimethyl-1H-pyrrole-3-carboxamide

EXAMPLE 218

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-1H-pyrrole-3-carboxamide

EXAMPLE 219

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl]-1H-pyrrole-3-carboxamide

EXAMPLE 220

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide

EXAMPLE 221

5-(5-Fluoro-2-{[(3,8)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-phenyl-1H-pyrrole-3-carboxamide

EXAMPLE 222

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-phenyl-1H-pyrrole-3-carboxamide

EXAMPLE 223

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-fluorophenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 224

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-fluorophenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 225

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N,1,2-trimethyl-1H-pyrrole-3-carboxamide

EXAMPLE 226

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-hydroxypyrimidin-5-yl)-1,2-dimethyl-N-phenyl-1H-pyrrole-3-carboxamide

EXAMPLE 227

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-hydroxypyrimidin-5-yl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 228

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-hydroxypyrimidin-5-yl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 229

5-(5-Fluoro-2-{[(18)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-hydroxypyrimidin-5-yl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 230

N-(5-Cyano-1-methyl-1H-pyrrol-3-yl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 8 and the compound of Preparation 3′ inStep A, and the compound of Preparation 19″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=66.43:67.09; % H=5.57:5.21; % N=11.62:11.48% Cl.=4.90:4.75.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₀H₃₉FN₆O₄

[M+H]⁺ calculated: 687.3097

[M+H]⁺ measured: 687.3073

EXAMPLE 231

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 232

5-(5-Fluoro-2-{[(3.8)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 233

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 234

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 235

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 236

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 237

1-Ethyl-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 238

1-Ethyl-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 239

1-Ethyl-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 240

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-(2-methoxyethyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 241

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-(2-methoxyethyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 242

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-(2-methoxyethyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 243

1-(2-Fluoroethyl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 244

1-(2-Fluoroethyl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 245

1-(2-Fluoroethyl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 246

1-(2,2-Difluoroethyl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 247

1-(2,2-Difluoroethyl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 248

1-(2,2-Difluoroethyl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 249

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 250

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 251

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 252

5-(5-Fluoro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-3-carboxamide

EXAMPLE 253

5-(5-Fluoro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-3-carboxamide

EXAMPLE 254

5-(5-Fluoro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-3-carboxamide

EXAMPLE 255

5-(5-Fluoro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-1-[2-(morpholin-4-yl)ethyl]-N-phenyl-1H-pyrrole-3-carboxamide

EXAMPLE 256

1-[2-(Dimethylamino)ethyl]-5-(5-fluoro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 257

1-[2-(Dimethylamino)ethyl]-5-(5-fluoro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-phenyl-1H-pyrrole-3-carboxamide

EXAMPLE 258

1-[2-(Dimethylamino)ethyl]-5-(5-fluoro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 259

1-[2-(Dimethylamino)ethyl]-5-(5-fluoro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 260

5-(5-Fluoro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 261

5-(5-Fluoro-2-{[(3R)-3-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 262

5-(5-Fluoro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 263

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 264

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 265

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 266

2-(Difluoromethyl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 267

2-(Difluoromethyl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 268

2-(Difluoromethyl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 269

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-(methoxymethyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 270

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-(methoxymethyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 271

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-(methoxymethyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 272

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-2-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 273

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 274

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 275

2-(2,2-Difluoroethyl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 276

2-(2,2-Difluoroethyl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 277

2-(2,2-Difluoroethyl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 278

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-(2-methoxyethyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 279

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-(2-methoxyethyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 280

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-(2-methoxyethyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 281

5-(5-Fluoro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-2-(morpholin-4-ylmethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 282

5-(5-Fluoro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(morpholin-4-ylmethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 283

5-(5-Fluoro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(morpholin-4-ylmethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 284

5-(5-Fluoro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-2-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-3-carboxamide

EXAMPLE 285

5-(5-Fluoro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-3-carboxamide

EXAMPLE 286

5-(5-Fluoro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-3-carboxamide

EXAMPLE 287

5-(5-Fluoro-2-{[(3S)-3-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 288

5-(5-Fluoro-2-{[(3S)-3-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 289

5-(5-Fluoro-2-{[(3S)-3-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 291

5-(2-{[(3S)-3-(Difluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 292

5-(2-{[(3S)-3-(Difluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 293

5-(5-Fluoro-2-{[(3S)-3-(fluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 294

5-(5-Fluoro-2-{[(3S)-3-(fluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 295

5-(5-Fluoro-2-{[(3S)-3-(fluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 296

5-(5-Fluoro-2-{[(3S)-3-(fluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 297

5-(5-Fluoro-2-{[(3S)-3-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolof 2,3-bi pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 298

5-(5-Fluoro-2-{[(3S)-3-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 299

5-(5-Fluoro-2-{[(3S)-3-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 300

5-(5-Fluoro-2-{[(3S)-3-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 301

5-(5-Fluoro-2-{[(3S)-3-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 302

5-(2-{[(3S)-3-(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 303

5-(2-{[(3S)-3-(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 304

5-(2-{[(3S)-3-(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 305

5-(2-{[(3S)-3-[(3-Cyanoazetidin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 306

5-(2-{[(3S)-3-[(3-Cyanoazetidin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 307

5-(2-{[(3S)-3-[(3-Cyanoazetidin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-5-fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 308

5-(5-Fluoro-2-{[(3S)-3-(1-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 309

5-(5-Fluoro-2-{[(3S)-3-(1-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 310

N-(1-Ethyl-1H-pyrazol-4-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 311

N-(1-Cyclopropyl-1H-pyrazol-4-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 312

N-(4-Hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-[1-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrrole-3-carboxamide

EXAMPLE 313

N-[1-(Difluoromethyl)-1H-pyrazol-4-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 314

N-(4-Hydroxyphenyl)-N-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-1,2-dimethyl-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 315

N-(4-Hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-1H-pyrrole-3-carboxamide

EXAMPLE 316

N-(4-Hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-[1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl]-1H-pyrrole-3-carboxamide

EXAMPLE 317

N-[1-(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 318

1,2-Dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-1H-pyrrole-3-carboxamide

EXAMPLE 319

1,2-Dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-1H-pyrrole-3-carboxamide

EXAMPLE 320

N-(4-Fluorophenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 321

N-(4-Fluorophenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 322

N-(4-Hydroxyphenyl)-N,1,2-trimethyl-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 323

N-(2-Hydroxypyrimidin-5-yl)-1,2-dimethyl-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-1H-pyrrole-3-carboxamide

EXAMPLE 324

N-(2-Hydroxypyrimidin-5-yl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 325

N-(2-Hydroxypyrimidin-5-yl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 326

N-(2-Hydroxypyrimidin-5-yl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 327

N-(5-Cyano-1-methyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 328

N-(4-Hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 329

N-(4-Hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 330

N-(4-Hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 331

N-(4-Hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 332

N-(4-Hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 333

1-Ethyl-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]-pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 334

1-Ethyl-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 335

N-(4-Hydroxyphenyl)-1-(2-methoxyethyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 336

N-(4-Hydroxyphenyl)-1-(2-methoxyethyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 337

1-(2-Fluoroethyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 338

1-(2-Fluoroethyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-0)-1H-pyrrole-3-carboxamide

EXAMPLE 339

1-(2,2-Difluoroethyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 340

1-(2,2-Difluoroethyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 341

N-(4-Hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 342

N-(4-Hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 343

N-(4-Hydroxyphenyl)-2-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 344

N-(4-Hydroxyphenyl)-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-3-carboxamide

EXAMPLE 345

N-(4-Hydroxyphenyl)-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-3-carboxamide

EXAMPLE 346

1-[2-(Dimethylamino)ethyl]-N-(4-hydroxyphenyl)-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 347

1-[2-(Dimethylamino)ethyl]-N-(4-hydroxyphenyl)-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 348

1-[2-(Dimethylamino)ethyl]-N-(4-hydroxyphenyl)-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 349

N-(4-Hydroxyphenyl)-1-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 350

N-(4-Hydroxyphenyl)-1-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-2-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 351

N-(4-Hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 352

2-(Difluoromethyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 353

N-(4-Hydroxyphenyl)-2-(methoxymethyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 354

N-(4-Hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-2-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 355

N-(4-Hydroxyphenyl)-1-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-2-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 356

N-(4-Hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-2-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 357

2-(2,2-Difluoroethyl)-N-(4-hydroxyphenyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 358

N-(4-Hydroxyphenyl)-2-(2-methoxyethyl)-1-methyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process describedin Step B of Example 49 using Example 88 as starting material, it beingunderstood that the product is finally dissolved in acetonitrile andconverted into salt form in 0.1M aqueous HCl solution. After alyophilisation step, the expected product is obtained in the form of asolid.

Elemental microanalysis: (%, theoretical:measured)

% C=65.80:64.71; % H=6.01:5.74; % N=10.23:10.03; % Cl−=4.32:6.47.

High-resolution mass spectrometry (ESI/+):

Empirical formula: C₄₅H₄₈N₆O₇

[M+H]⁺ calculated: 785.3657

[M+H]⁺ measured: 785.3658

EXAMPLE 359

N-(4-Hydroxyphenyl)-1-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(morpholin-4-ylmethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 360

N-(4-Hydroxyphenyl)-1-methyl-5-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(morpholin-4-ylmethyl)-1H-pyrrole-3-carboxamide

EXAMPLE 361

N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 362

N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 363

N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(6-{[(3S)-3-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 364

5-(6-{[(3S)-3-(Difluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 365

5-(6-{[(3S)-3-(Difluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 366

5-(6-{[(3S)-3-(Difluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 367

5-(6-{[(3S)-3-(Fluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 368

5-(6-{[(3S)-3-(Fluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 369

5-(6-{[(3S)-3-(Fluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 370

5-(6-{[(3S)-3-[(9aS)-Hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 371

5-(6-{[(3S)-3-[(9aS)-Hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 372

5-(6-{[(3S)-3-[(9a)-Hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 373

5-(6-{[(3S)-3-[(9aR)-Hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 374

5-(6-{[(3S)-3-[(9aR)-Hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 375

5-(6-{[(3S)-3-[(9aR)-Hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 376

5-(6-{[(3S)-3-(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 377

546-{[(3S)-3-(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 378

5-(6-{[(3S)-3-(Aminomethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 379

5-(6-{[(3S)-3-[(3-Cyanoazetidin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 380

5-(6-{[(3S)-3-[(3-Cyanoazetidin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 381

5-(6-{[(3S)-3-[(3-Cyanoazetidin-1-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 382

N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(1-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 383

N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]-pyridin-5-yl)-5-(6-{[(3S)-3-(1-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamide

EXAMPLE 384

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(pyridin-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=67.28:67.73; % H=5.65:5.30; % N=10.06:9.41% Cl−=5.09:5.79

EXAMPLE 385

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₁H₄₁ClN₆O₄

[M+H]⁺ calculated: 713.3253

[M+H]⁺ measured: 713.3272

EXAMPLE 386

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

Step A:N-[4-[tert-Butyl(dimethyl)silyl]oxyphenyl]-5-[5-chloro-2-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-N-(5-cyano-1,2-dimethylpyrrol-3-yl)-1,2-dimethyl-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the compound of Preparation 18″ in Step C.

IR: ν —CN—: 2210 cm⁻¹; ν —C═O—: 1631 cm⁻¹

Step B:5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The compound of Step A is deprotected in accordance with the protocoldescribed in Step D of Example 1. The product thereby obtained isfinally subjected to a step of conversion into salt form in the presenceof HCl in ether. After filtration and lyophilisation in a mixture ofacetonitrile/water, the expected product is obtained.

¹H NMR (500 MHz, dmso-d6) δ ppm: 11.2 (bs, 1H), 9.39 (bs, 1H), 7.83 (d,1H), 7.54 (d, 1H), 7.33 (s, 1H), 7.14 (m, 2H), 7 (m, 2H), 6.8 (d, 2H),6.62 (d, 2H), 6.57 (bs, 1H), 5.26 (s, 1H), 5.26 (m, 1H), 4.64/4.03 (AB,2H), 4.01/3.92 (2m, 4H), 3.75/3.43/3.15/3.02 (4m, 4H), 3.59 (s, 3H),3.3/3.5 (2m, 2H), 2.97 (s, 3H), 2.69/2.52 (dd+d, 2H), 2.06 (s, 3H), 1.91(s, 3H)

Elemental microanalysis: (%, theoretical:measured)

% C %=65.34:65.50; % H=5.62:5.15; % N=11.15:10.84% Cl−=4.70:4.44.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₁H₄₁ClN₆O₄

[M+H]⁺ calculated: 717.2952

[M+H]⁺ measured: 717.2951

EXAMPLE 387

N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=66.62:66.36; % H=5.59:5.62; % N=10.84:10.72% Cl−=4.57:4.55.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₃H₄₂N₆O₆

[M+H]⁺ calculated: 739.3239

[M+H]⁺ measured: 739.3241

EXAMPLE 388

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamidedihydrochloride

The title compound is obtained in accordance with the process describedin Step B of Example 49 using Example 71 as starting material, it beingunderstood that the product is finally subjected to a step of conversioninto salt form in the presence of 1M HCl in ether. After filtration andlyophilisation in a mixture of acetonitrile/water, the expected compoundis obtained.

Elemental microanalysis: (%, theoretical:measured)

% C=62.73:62.96; % H=5.64:4.95; % N=10.45:10.32; % Cl=13.23:12.91.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₂H₄₃ClN₆O₄

[M+H]⁺ calculated: 731.3107

[M+H]⁺ measured: 731.3111

EXAMPLE 389

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

The procedure is in accordance with the general protocol of Example 1using the appropriate Preparations. The product obtained is finallydissolved in acetonitrile and converted into salt form using 0.1Maqueous HCl solution. After a lyophilisation step, the expected compoundis obtained in the form of a solid.

Elemental microanalysis: (%, theoretical:measured)

% C=65.88:66.28; % H=5.53:5.15; % N=10.98:10.95; % Cl−=4.63:4.47.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS):

Empirical formula: C₄₂H₄₁ClN₆O₄

[M+H]⁺ calculated: 729.2951

[M+H]⁺ measured: 729.2954

EXAMPLE 390

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-phenyl-1H-pyrrole-3-carboxamide

The procedure is in accordance with the general protocol of Example 1using the appropriate Preparations, it being understood that Step D isnot carried out. The expected product is obtained in free base form.

Elemental microanalysis: (%, theoretical:measured)

% C=70.72:69.77; % H=5.79:5.96; % N=11.78:11.43.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₂H₄₁ClNO₆O₃

[M+H]⁺ calculated: 713.3001

[M+H]⁺ measured: 713.2998

EXAMPLE 391

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=65.88:65.69; % H=5.33:4.87; % N=10.98:10.86; % Cl−=4.63:4.51.

High-resolution mass spectrometry (ESI+−/FIA):

Empirical formula: C₄₂H₄₁ClN₆O₄

[M+H]⁺ calculated: 729.2951

[M+H]⁺ measured: 729.2953

EXAMPLE 392

5-(5-Chloro-2-{[(3R)-3-[3-(morpholin-4-yl)propyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-phenyl-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=68.19:68.33; % H=6.00:5.49; % N=10.78:10.71; % Cl−=4.55:4.46; %Cl=9.58:9.78.

High-resolution mass spectrometry (ESI+−/FIA):

Empirical formula: C₄₂H₄₃ClN₄O₄

[M+H]⁺ calculated: 703.3046

[M+H]⁺ measured: 703.3042

EXAMPLE 393

5-(5-Chloro-2-{[(3R)-3-[3-(morpholin-4-yl)propyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

High-resolution mass spectrometry (ESI+−/FIA):

Empirical formula: C₄₄H₄₅ClN₆O₄

[M+H]⁺ calculated: 757.3264

[M+H]⁺ measured: 757.3263

EXAMPLE 394

5-(5-Chloro-2-{[(3R)-3-[3-(morpholin-4-yl)propyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process describedin Step B of Example 49 using Example 393 as starting material, it beingunderstood that the product is not subjected to the step of conversioninto salt form.

Elemental microanalysis: (%, theoretical:measured)

% C=69.60:69.56; % H=6.21:6.24; % N=11.07:11.08.

High-resolution mass spectrometry (ESI+−/FIA):

Empirical formula: C₄₄H₄₇ClN₆O₄

[M+H]⁺ calculated: 759.3420

[M+H]⁺ measured: 759.3422

EXAMPLE 395

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-cyano-4-methoxyphenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The procedure is in accordance with the general protocol of Example 1using the appropriate Preparations. The product obtained is finallydissolved in acetonitrile and converted into salt form using 0.1Maqueous HCl solution. After a lyophilisation step, the expected compoundis obtained in the form of a solid.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS):

Empirical formula: C₄₂H₄₀ClN₅O₅

[M+H]⁺ calculated: 730.2791

[M+H]⁺ measured: 730.2790

EXAMPLE 396

N-(3-Fluoro-4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 11 and(3S)-3-(4-morpholinylmethyl)-1,2,3,4-tetrahydroisoquinoline (seePreparation 3′) in Step A, and the compound of Preparation 20″ in StepC. The product obtained is finally subjected to a step of conversioninto salt form in the presence of 1M HCl in ether. After filtration andlyophilisation in a mixture of acetonitrile/water, the expected compoundis obtained.

Elemental microanalysis: (%, theoretical:measured)

% C=65.79:65.43; % H=5.39:5.19; % N=11.31:11.21; % Cl−=4.77:4.34.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS):

Empirical formula: C₃₉H₃₉FN₆O₆

[M+H]⁺ calculated: 707.2988

[M+H]⁺ measured: 707.2988

EXAMPLE 397

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(2-methoxypyrimidin-5-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamide

High-resolution mass spectrometry (ESI+):

Empirical formula: C₃₉H₃₉ClN₆O₅

[M+H]⁺ calculated: 707.2743

[M+H]⁺ measured: 707.2746

EXAMPLE 398

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-cyanophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=66.85:66.75; % H=5.34:5.42; % N=9.51:9.73; % Cl=9.62:9.67; %Cl.=4.81:4.71.

High-resolution mass spectrometry (ESI+−/FIA/HR, ESI−/FIA):

Empirical formula: C₄₁H₃₈ClN₅O₄

[M+H]⁺ calculated: 700.2685

[M+H]⁺ measured: 700.2686

EXAMPLE 399

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-fluoro-4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and(3S)-3-(4-morpholinylmethyl)-1,2,3,4-tetrahydroisoquinoline (seePreparation 3′) in Step A, and the compound of Preparation 20″ in StepC. The product obtained is finally subjected to a step of conversioninto salt form in the presence of 1M HCl in ether. After filtration andlyophilisation in a mixture of acetonitrile/water, the expected compoundis obtained.

Elemental microanalysis: (%, theoretical:measured)

% C=62.21:61.32; % H=5.36:5.18; % N=11.46:11.14; % Cl=9.66:10.16; %Cl.=4.83:5.23.

High-resolution mass spectrometry (ESI+−/FIA/HR, ESI−/FIA):

Empirical formula: C₃₈H₃₈ClFN₆O₄

[M+H]⁺ calculated: 697.2700

[M+H]⁺ measured: 697.2704

EXAMPLE 400

Methyl2-[{[5-(5-chloro-2-{[(36)-3-(morpholin-4-ylmethyl)-3,4-dihydro-isoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrol-3-yl]carbonyl}(4-hydroxyphenyl)amino]pyridine-4-carboxylatehydrochloride

The title compound is a secondary product which forms in the course ofsynthesis of Example 110 (in the final Step before the step ofconversion into salt form) owing to hydrolysis of the nitrile functioninto a methyl ester function. The compound is separated from that ofExample 110 by chromatography over silica gel in a mixture of methanoland dichloromethane.

Elemental microanalysis: (%, theoretical:measured)

% C=63.90:64.43; % H=5.36:5.01; % N=9.09:9.34; % Cl.=4.60:4.46.

High-resolution mass spectrometry (ESI+/R and ESI−/LR):

Empirical formula: C₄₁H₄₀ClN₅O₆

[M+H]⁺ calculated: 734.2740

[M+H]⁺ measured: 734.2743

EXAMPLE 401

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-cyano-4-fluorophenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=65.25:64.23; % H=5.07:4.71; % N=9.28:9.36; % Cl=9.40:9.59; %Cl.=4.70:4.50.

High-resolution mass spectrometry (ESI+−/FIA/HR, ESI−/FIA):

Empirical formula: C₄₁H₃₇ClFN₅O₄

[M+H]⁺ calculated: 718.2591

[M+H]⁺ measured: 718.2593

EXAMPLE 402

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-{1-[(3Sor R)-tetrahydrofuran-3-yl]-1H-pyrazol-4-yl}-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=65.20:65.92; % H=5.87:5.78; % N=11.13:10.36.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₁H₄₃FN₆O₅

[M+H]⁺ calculated: 719.3359

[M+H]⁺ measured: 719.3362

and

EXAMPLE 403

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-{1-[(3Ror S)-tetrahydrofuran-3-yl]-1H-pyrazol-4-yl}-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=65.20:66.04; % H=5.87:5.87; % N=11.13:10.62; % Cl.=4.69:4.76.

High-resolution mass spectrometry (ESI/+):

Empirical formula: C₄₁H₄₃FN₆O₅

[M+H]⁺ calculated: 719.3359

[M+H]⁺ measured: 719.3350

The compounds of Examples 402 and 403 are obtained in accordance withthe process of Example 1 using the acid of Preparation 8 and thecompound of Preparation 3′ in Step A, and the compound of Preparation22″ in Step C. The diastereoisomers obtained are separated by chiralchromatography and then converted into salt form and lyophilised asdescribed in the general process to yield the title compounds.

EXAMPLE 404

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(2-cyanopyrimidin-4-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

EXAMPLE 405

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(pyridazin-4-yl)-1H-pyrrole-3-carboxamidedihydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the appropriate amine in Step C, it being understood thatStep D is not carried out. The compound obtained is converted into saltform and lyophilised as described in the general process to obtain thetitle compound.

High-resolution mass spectrometry (ESI+−/FIA/HR, ESI−/FIA):

Empirical formula: C₄₀H₃₉ClN₈O₃

[M+H]⁺ calculated: 715.2906

[M+H]⁺ measured: 715.2909

EXAMPLE 406

N-(5-Cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 25 and the compound of Preparation 3′ inStep A, and the compound of Preparation 18″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=68.46:68.27; % H=6.03:5.12; % N=11.68:11.75; % Cl.=4.93:4.73.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS, ESI−/FIA):

Empirical formula: C₄₁H₄₂N₆O₄

[M+H]⁺ calculated: 683.3340

[M+H]⁺ measured: 683.3334

EXAMPLE 407

N-(3-Fluoro-4-hydroxyphenyl)-5-(5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 12 and the compound of Preparation 3′ inStep A, and the compound of Preparation 20″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=64.23:63.94; % H=5.80:5.00; % N=11.52:11.56; % Cl.=4.86:4.99.

High-resolution mass spectrometry (ESI+−/FIA/HR and MS/MS, ESI−/FIA):

Empirical formula: C₃₉H₄₁FN₆O₅

[M+H]⁺ calculated: 693.3195

[M+H]⁺ measured: 693.3191

EXAMPLE 408

N-(5-Cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-5-(5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 12 and the compound of Preparation 3′ inStep A, and the compound of Preparation 18″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=67.32:67.30; % H=6.05:5.28; % N=11.22:11.15; % Cl.=4.73:4.59.

High-resolution mass spectrometry (ESI+−/FIA/HR and ESI−/FIA):

Empirical formula: C₄₂H₄₄N₆O₅

[M+H]⁺ calculated: 713.3446

[M+H]⁺ measured: 713.3443

EXAMPLE 409

N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]-pyridin-5-yl)-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 25 and the compound of Preparation 3′ inStep A, and the compound of Preparation 11″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=68.98:68.95; % H=5.93:4.76; % N=11.49:11.43.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS):

Empirical formula: C₄₂H₄₂N₆O₄

[M+H]⁺ calculated: 695.3340

[M+H]⁺ measured: 695.3341

EXAMPLE 410

N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process describedin Step B of Example 49 using Example 409 as starting material. Thecompound obtained is converted into salt form and lyophilised asdescribed in the general process to obtain the title compound.

High-resolution mass spectrometry (ESI/FIA/HR and ESI−/FIA):

Empirical formula: C₄₂H₄₄N₆O₄

[M+H]⁺ calculated: 6973497

[M+H]⁺ measured: 697.3497

EXAMPLE 411

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-2-methyl-N-(1-methyl-1H-pyrazol-4-yl)-1-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example96 using the acid of Preparation 30, the compound of Preparation 1′, andthe compound of Preparation 1″. The compound obtained is converted intosalt form and lyophilised as described in the general process to obtainthe title compound.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS):

Empirical formula: C₃₉H₄₁ClN₆O₄

[M+H]⁺ calculated: 693.2951

[M+H]⁺ measured: 693.2947

EXAMPLE 412

5-(5-Chloro-2-{[(3R)-3-[3-(morpholin-4-yl)propyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 6′ inStep A, and the compound of Preparation 18″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=66.06:65.61; % H=5.93:5.22; % N=10.75:10.69; % Cl.=4.53:4.68.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS, ESI−/FIA):

Empirical formula: C₄₃H₄₅ClN₆O₄

[M+H]⁺ calculated: 745.3264

[M+H]⁺ measured: 745.3260

EXAMPLE 413

N-(5-Cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(7-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}-2,3-dihydro-1,4-benzodioxin-6-yl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 13 and the compound of Preparation 3′ inStep A, and the compound of Preparation 18″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=66.44:66.40; % H=5.83:4.84; % N=10.81:10.79; % Cl.=4.56:4.22.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS, ESI−/FIA):

Empirical formula: C₄₃H₄₄N₆O₆

[M+H]⁺ calculated: 741.3395

[M+H]⁺ measured: 741.3397

EXAMPLE 414

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(5-methyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the appropriate amine in Step C. The compound obtained isconverted into salt form and lyophilised as described in the generalprocess to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=64.23:64.38; % H=5.39:5.25; % N=12.79:12.62; % Cl.=4.62:4.39.

High-resolution muss spectrometry (ESI/FIA/HR and MS/MS, ESI−/FIA):

Empirical formula: C₄₁H₄₀ClN₇O₄

[M+H]⁺ calculated: 730.2903

[M+H]⁺ measured: 730.2904

EXAMPLE 415

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1-methyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 3 and the compound of Preparation 3′ inStep A, and the compound of Preparation 18″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=64.95:65.14; % H=5.45:5.34; % N=11.36:11.36; % Cl.=4.79:4.67.

High-resolution mass spectrometry (ESI+−/FIA/HR, ESI−/FIA):

Empirical formula: C₄₀H₃₉ClN₆O₄

[M+H]⁺ calculated: 703.2794

[M+H]⁺ measured: 703.2795

EXAMPLE 416

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(trideuteriomethyl)-1H-pyrazol-4-yl]-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the compound of Preparation 25″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=63.51:63.41; % H=5.63:5.42; % N=11.69:11.61; % Cl.=4.93:4.85.

High-resolution mass spectrometry (ESI+−/FIA/HR, ESI−/FIA):

Empirical formula: C₃₈H₃₆ClD₃N₆O₄

[M+H]⁺ calculated: 682.2982

[M+H]⁺ measured: 682.2986

EXAMPLE 417

N-(5-Cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-5-(4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 31 and the compound of Preparation 3′ inStep A, and the compound of to Preparation 18″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=67.32:67.56; % H=6.05:5.84; % N=11.22:11.21; % Cl.=4.73:4.71.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS, ESI−/FIA):

Empirical formula: C₄₂H₄₄N₆O₅

[M+H]⁺ calculated: 713.3446

[M+H]⁺ measured: 713.3446

EXAMPLE 418

N-(4-Hydroxyphenyl)-5-(4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 31 and the compound of Preparation 3′ inStep A, and the compound of Preparation 1″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=65.86:65.51; % H=6.09:6.09; % N=11.82:11.73; % Cl.=4.98:5.14.

High-resolution mass spectrometry (ESI/FIA/HR, ESI−/FIA):

Empirical formula: C₃₉H₄₂N₆O₅

[M+H]⁺ calculated: 675.3289

[M+H]⁺ measured: 675.3286

EXAMPLE 419

N-(3-Cyanophenyl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 8 and the compound of Preparation 3′ inStep A, and the compound of Preparation 41″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₁H₃₈FN₅O₄

[M+H]⁺ calculated: 684.2988

[M+H]⁺ measured: 684.2975

EXAMPLE 420

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(trideuteriomethyl)-1H-pyrazol-4-yl]-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 8 and the compound of Preparation 3′ inStep A, and the compound of Preparation 25″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

High-resolution mass spectrometry (ESI/+):

Empirical formula: C₃₈D₃H₃₆FN₆O₄

[M+H]⁺ calculated: 666.3285

[M+H]⁺ measured: 666.3265

EXAMPLE 421

N-(5-Cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 8 and the compound of Preparation 3′ inStep A, and the compound of Preparation 18″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

High-resolution muss spectrometry (ESI/FIA/HR and MS/MS):

Empirical formula: C₄₁H₄₁FN₆O₄

[M+H]⁺ calculated: 701.3246

[M+H]⁺ measured: 701.3282

EXAMPLE 422

N-(4-Hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 25 and the compound of Preparation 3′ inStep A, and the compound of Preparation 1″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=67.00:67.47; % H=6.07:5.54; % N=12.34:12.46; % Cl.=0.5.20:4.58.

High-resolution mass spectrometry (ESI+−/FIA/HR, ESI−/FIA):

Empirical formula: C₃₈H₄₀N₆O₄

[M+H]⁺ calculated: 645.3184

[M+H]⁺ measured: 645.3182

EXAMPLE 423

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 8 and the compound of Preparation 3′ inStep A, and the compound of Preparation 26″ in Step C.

Elemental microanalysis: (%, theoretical:measured)

% C=68.17:67.82; % H=5.86:5.97; % N=11.92:11.48.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS):

Empirical formula: C₄₀H₄₁FN₆O₅

[M+H]⁺ calculated: 705.3202

[M+H]⁺ measured: 705.3207

EXAMPLE 424

N-(4-Hydroxyphenyl)-N-(2-methoxypyrimidin-5-yl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 25 and the compound of Preparation 3′ inStep A, and the compound of Preparation 12″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=66.05:65.63; % H=5.83:5.45; % N=11.85:11.93; % Cl.=5.00:4.91.

High-resolution mass spectrometry (ESI+−/FIA/HR, ESI−/FIA):

Empirical formula: C₃₉H₄₀N₆O₅

[M+H]⁺ calculated: 673.3133

[M+H]⁺ measured: 673.3129

EXAMPLE 425

N-(3-Cyano-5-methoxyphenyl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 8 and the compound of Preparation 3′ inStep A, and the appropriate amine in Step C. The compound obtained isconverted into salt form and lyophilised as described in the generalprocess to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=67.25:66.55; % H=5.51:5.28; % N=9.33:8.55% Cl.=4.73:4.67

EXAMPLE 426

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(2-methoxypyrimidin-5-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 8 and the compound of Preparation 3′ inStep A, and the compound of Preparation 12″ in Step C.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS):

Empirical formula: C₃₉H₃₉FN₆O₅

[M+H]⁺ calculated: 691.3038

[M+H]⁺ measured: 691.3060

EXAMPLE 427

N-(3-Cyano-4-methoxyphenyl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 8 and the compound of Preparation 3′ inStep A, and the appropriate amine in Step C. The compound obtained isconverted into salt form and lyophilised as described in the generalprocess to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=67.24:66.41; % H=5.51:5.35; % N=9.33:8.97% Cl.=4.73:4.81

EXAMPLE 428

N-(5-Cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-(4-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 26 and the compound of Preparation 3′ inStep A, and the compound of Preparation 18″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=66.79:66.97; % H=5.74:5.36; % N=11.40:11.45; % Cl.=4.81:4.53.

High-resolution mass spectrometry (ESI+−/FIA/HR, ESI−/FIA):

Empirical formula: C₄₁H₄₁FN₆O₄

[M+H]⁺ calculated: 701.3246

[M+H]⁺ measured: 701.3245

EXAMPLE 429

N-(5-Cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-(4-fluoro-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 27 and the compound of Preparation 3′ inStep A, and the compound of Preparation 18″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=65.75:65.43; % H=5.78:5.57; % N=10.95:10.81; % Cl.=4.62:4.54.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS, ESI−/FIA):

Empirical formula: C₄₂H₄₃FN₆O₅

[M+H]⁺ calculated: 731.3352

[M+H]⁺ measured: 731.3351

EXAMPLE 430

5-(5-Chloro-2-{[3-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]-pyridin-5-yl)-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and racemic3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline in Step A, and thecompound of Preparation 11″ in Step C.

High-resolution mass spectrometry (ESI+−/FIA/HR and MS/MS, ESI−/FIA):

Empirical formula: C₃₈H₃₁ClF₃N₅O₃

[M+H]⁺ calculated: 698.2140

[M+H]⁺ measured: 698.2144

EXAMPLE 431

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=64.19:64.37; % H=5.80:5.18; % N=11.52:11.55; % Cl.=4.86:4.68.

High-resolution mass spectrometry (ESI+−/FIA/HR, ESI−/FIA):

Empirical formula: C₃₉H₄₁ClN₆O₄

[M+H]⁺ calculated: 693.2951

[M+H]⁺ measured: 693.2952

and

EXAMPLE 432

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(1,5-dimethyl-1H-pyrazol-4-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=64.19:64.43; % H=5.80:5.22; % N=11.52:11.60; % Cl.=4.86:4.66.

High-resolution mass spectrometry (ESI+−/FIA/HR, ESI−/FIA):

Empirical formula: C₃₉H₄₁ClN₆O₄

[M+H]⁺ calculated: 693.2951

[M+H]⁺ measured: 693.2953

The compounds of Examples 431 and 432 are obtained in accordance withthe process of Example 1 using the acid of Preparation 1 and thecompound of Preparation 3′ in Step A, and the mixture of Preparation 27″in Step C. At the end of Step D, the isomers are separated bypreparative HPLC using acetonitrile and water-TFA as eluants. Afterevaporating off the solvent and neutralising with sodium bicarbonate,the products are subjected to a step of conversion into salt form in thepresence of 1M HCl in ether. After filtration and lyophilisation in amixture of acetonitrile/water, the title products are obtained.

EXAMPLE 433

N-(5-Cyano-1-methyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 25 and the compound of Preparation 3′ inStep A, and the compound of Preparation 19″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=68.12:68.29; % H=5.86:5.40; % N=11.92:12.05; % Cl.=5.03:4.92.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS):

Empirical formula: C₄₀H₄₀N₆O₄

[M+H]⁺ calculated: 669.3184

[M+H]⁺ measured: 669.3184

EXAMPLE 434

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process describedin Step B of Example 49 using Example 385 as starting material. Thecompound obtained is converted into salt form and lyophilised asdescribed in the general process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=67.15:68.03; % H=5.90:5.50; % N=11.19:10.59% Cl.=4.72:5.55

EXAMPLE 435

N-(4-Cyanopyridin-2-yl)-5-(5-fluoro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 14 and the compound of Preparation 3′ inStep A, and the appropriate amine in Step C. The compound obtained isconverted into salt form and lyophilised as described in the generalprocess to obtain the title compound.

High-resolution mass spectrometry (ESI+−/FIA/HR, ESI−/FIA):

Empirical formula: C₄₁H₃₉FN₆O₅

[M+H]⁺ calculated: 715.3039

[M+H]⁺ measured: 715.3040

EXAMPLE 436

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyanothiophen-2-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the appropriate amine in Step C. The compound obtained isconverted into salt form and lyophilised as described in the generalprocess to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=63.07:63.09; % H=5.02:4.78; % N=9.43:9.35; % S=4.32:4.09: %Cl.=4.77:4.59.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS, ESI+−/FIA):

Empirical formula: C₃₉H₃₆ClN₅O₄S

[M+H]⁺ calculated: 706.2249:

[M+H]⁺ measured: 706.2250

EXAMPLE 437

N-(3-Cyano-4-fluorophenyl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 8 and the compound of Preparation 3′ inStep A, and the appropriate amine in Step C. The compound obtained isconverted into salt form and lyophilised as described in the generalprocess to obtain the title compound.

High-resolution mass spectrometry (ES+):

Empirical formula: C₄₁H₃₇F₂N₅O₄

[M+H]⁺ calculated: 702.2894

[M+H]⁺ measured: 702.2886

EXAMPLE 438

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(pyrazin-2-yl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the appropriate amine in Step C. The compound obtained isconverted into salt form and lyophilised as described in the generalprocess to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=63.95:63.96; % H=5.37:5.17; % N=11.78:11.61; % Cl.=4.97:4.57

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₃₈H₃₇ClN₆O₄

[M+H]⁺ calculated: 677.2638

[M+H]⁺ measured: 677.2639

EXAMPLE 439

5-(5-Fluoro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(2-methoxypyrimidin-5-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 14 and the compound of Preparation 3′ inStep A, and the compound of Preparation 12″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS, ESI−/FIA):

Empirical formula: C₄₀H₄₁FN₆O₆

[M+H]⁺ calculated: 721.3144

[M+H]⁺ measured: 721.3144

EXAMPLE 440

N-(5-Cyano-1,2-dimethyl-1H-pyrrol-3-yl)-5-(5-fluoro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 14 and the compound of Preparation 3′ inStep A, and the compound of Preparation 18″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=65.75:65.98; % H=5.78:5.50; % N=10.95:10.87; % Cl.=4.62:4.42.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₄₂H₄₃FN₆O₅

[M+H]⁺ calculated: 731.3352

[M+H]⁺ measured: 731.3353

EXAMPLE 441

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-1,2-dimethyl-N-phenyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the compound of Preparation 29″ in Step C, it beingunderstood that Step D is not carried out. The compound obtained isconverted into salt form and lyophilised as described in the generalprocess to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=66.75:66.44; % H=5.74:5.59; % N=11.39:11.45; % Cl.=4.81:4.43.

High-resolution mass spectrometry (ESP/HR, ESI−/LR):

Empirical formula: C₄₁H₄₁ClN₆O₃

[M+H]⁺ calculated: 701.3001

[M+H]⁺ measured: 701.2998

EXAMPLE 442

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyanothiophen-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the compound of Preparation 42″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=63.07:63.14; % H=5.02:4.87; % N=9.43:9.41; % S=4.32:4.24; %Cl.=4.77:4.57.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₃₉H₃₆ClN₅O₄S

[M+H]⁺ calculated: 706.2249

[M+H]⁺ measured: 706.2252

EXAMPLE 443

5-(5-Fluoro-4-hydroxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-phenyl-1H-pyrrole-3-carboxamide

Step A:5-(5-Fluoro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-phenyl-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example1 (Steps A to C) using the acid of Preparation 28 and the compound fromPreparation 3′ in Step A, and the compound of Preparation 30″ in Step C.

Step B:5-(5-Fluoro-4-hydroxy-2-{[(3N)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-phenyl-1H-pyrrole-3-carboxamide

To a solution of the compound of Step A (1 g; 1.37 mmol) in anhydrousdichloromethane (10 mL) there is added, dropwise at 0° C., a 1M solutionof boron tribromide in dichloromethane (1.8 mL; 1.8 mmol). Afterstirring for 15 hours at ambient temperature, the reaction mixture ispoured dropwise into a solution of ethanol (15 mL) at −10° C. Afterstirring for one hour, saturated aqueous sodium bicarbonate solution isadded, and the reaction mixture is extracted with dichloromethane. Afterdrying over MgSO₄, the residue is purified on a silica gel column usinga mixture of dichloromethane and methanol as eluant to yield theexpected product.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₄₂H₄₁FN₆O₄

[M+H]⁺ calculated: 713.3246

[M+H]⁺ measured: 713.3244

EXAMPLE 444

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(5-methoxypyrazin-2-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the appropriate amine in Step C. The compound obtained isconverted into salt form and lyophilised as described in the generalprocess to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=62.99:62.72; % H=5.42:5.24; % N=11.30:11.19; % Cl.=4.77:4.67.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₃₉H₃₉ClN₆O₅

[M+H]⁺ calculated: 707.2743

[M+H]⁺ measured: 707.2747

EXAMPLE 445

5-(5-Chloro-2-{[(35)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(trideuteriomethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrrole-3-carboxamidehydrochloride

Step A:5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(trideuteriomethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrrole-3-carboxamide

The intermediate is obtained in accordance with the process of Example 1using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the compound of Preparation 31″ in Step C.

Step B:5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(trideuteriomethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-pyrrole-3-carboxamidehydrochloride

The procedure is in accordance with the protocol described in Step B ofExample 49, it being understood that the product is then subjected to astep of conversion into salt form in the presence of 1M HCl in ether.After filtration and lyophilisation in a mixture of acetonitrile/water,the title product is obtained.

Elemental microanalysis: (%, theoretical:measured)

% C=65.45:65.33; % H=5.78:5.59; % N=10.90:10.82; % Cl.=4.60:4.28.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₄₂H₄₀ClD₃N₆O₄

[M+H]⁺ calculated: 734.3295

[M+H]⁺ measured: 734.3300

EXAMPLE 446

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-fluoropyrazin-2-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the appropriate amine in Step C. The compound obtained isconverted into salt form and lyophilised as described in the generalprocess to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=62.28:62.16; % H=5.10:4.97; % N=11.04:11.35; % Cl.=4.85:4.48.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₃₈H₃₆ClFN₆O₄

[M+H]⁺ calculated: 695.2543

[M+H]⁺ measured: 695.2545

EXAMPLE 447

5-(4-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 26 and the compound of Preparation 3′ inStep A, and the compound of Preparation 1″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=65.28:65.27; % H=5.77:5.51; % N=12.02:1.90; % Cl.=5.07:4.74.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₃₈H₃₉FN₆O₄

[M+H]⁺ calculated: 663.3090

[M+H]⁺ measured: 663.3084

EXAMPLE 448

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-[5-cyano-1-(trideuteriomethyl)-1H-pyrrol-3-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the compound of Preparation 32″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=64.69:64.23; % H=5.45:5.47; % N=11.32:11.16; % Cl.=4.77:4.56.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₄₀H₃₆ClD₃N₆O₄

[M+H]⁺ calculated: 706.2982

[M+H]⁺ measured: 706.2985

EXAMPLE 449

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-[5-cyano-2-methyl-1-(trideuteriomethyl)-1H-pyrrol-3-yl]-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the compound of Preparation 33″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=65.07:64.55; % H=5.62:5.51; % N=11.11:10.98; % Cl.=4.68:4.58.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₄₁H₃₈ClD₃N₆O₄

[M+H]⁺ calculated: 720.3139

[M+H]⁺ measured: 720.3143

EXAMPLE 450

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(3-cyano-1-methyl-1H-pyrazol-5-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the compound of Preparation 34″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=63.24:62.62; % H=5.31:5.09; % N=13.24:13.04; % Cl.=4.79:4.37.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₃₉H₃₈ClN₇O₄

[M+H]⁺ calculated: 704.2747

[M+H]⁺ measured: 704.2747

EXAMPLE 451

5-(5-Fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 8 and the compound of Preparation 3′ inStep A, and the compound of Preparation 17″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=65.64:66.28; % H=5.51:5.45; % N=13.07:12.17% Cl.=4.73:5.51

EXAMPLE 452

N-(1,3-Dimethyl-1H-pyrazol-4-yl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=65.68:64.77; % H=5.94:5.55; % N=11.78:10.69% Cl.=4.97:6.48

and

EXAMPLE 453

N-(1,5-Dimethyl-1H-pyrazol-4-yl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

Elemental microanalysis: (%, theoretical:measured)

% C=65.68:65.43; % H=5.94:5.62; % N=11.78:10.95% Cl.=4.97:5.60

The compounds of Examples 452 and 453 are obtained in accordance withthe process of Example 1 using the acid of Preparation 8 and thecompound of Preparation 3′ in Step A, and the mixture of Preparation 27″in Step C. At the end of Step D, the isomers are separated bypreparative HPLC using acetonitrile and water-TFA as eluants. Afterevaporating off the solvent and neutralising with sodium bicarbonate,the products are subjected to a step of conversion into salt form in thepresence of 1M HCl in ether. After filtration and lyophilisation in amixture of acetonitrile/water, the title products are obtained.

EXAMPLE 454

5-(5-Chloro-2-{[3-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example1 using the acid from Preparation 1 and racemic3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline in Step A, and thecompound of Preparation 18″ in Step C.

Elemental microanalysis: (%, theoretical:measured)

% C=64.77:64.81; % H=4.55:4.52; % N=10.21:10.33.

High-resolution mass spectrometry (ESI+/HR):

Empirical formula: C₃₇H₃₁ClF₃N₅O₃

[M+H]⁺ calculated: 686.2140

[M+H]⁺ measured: 686.2145

EXAMPLE 455

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)-N-{5-cyano-2-methyl-1-[2-(morpholin-4-yl)ethyl]-1H-pyrrol-3-yl}-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 1′ inStep A, and the compound of Preparation 35″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=65.71:66.07; % H=5.78:5.82; % N=10.95:10.66; % Cl.=4.62:4.45.

High-resolution mass spectrometry (ESI+/HR,

Empirical formula: C₄₂H₄₃ClN₆O₄

[M+H]⁺ calculated: 731.3107

[M+H]⁺ measured: 731.3109

EXAMPLE 456

5-(5-Chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-{2-[2-(morpholin-4-yl)-ethoxy]pyrimidin-5-yl}-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 1′ inStep A, and the compound of Preparation 36″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=63.41:63.51; % H=5.59:5.26; % N=11.09:11.10; % Cl.=4.68:4.46.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₄₀H₄₁ClN₆O₅

[M+H]⁺ calculated: 721.2900

[M+H]⁺ measured: 721.2907

EXAMPLE 457

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(6-cyano-5-methoxypyridin-2-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the appropriate amine in Step C. The compound obtained isconverted into salt form and lyophilised as described in the generalprocess to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=64.15:63.95; % H=5.25:4.79; % N=10.95:10.97; % Cl.=4.62:4.22.

High-resolution mass spectrometry (ESI+/HR):

Empirical formula: C₄₁H₃₉ClN₆O₅

[M+H]⁺ calculated: 731.2743

[M+H]⁺ measured: 731.2746

EXAMPLE 458

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,4-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the compound of Preparation 37″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=65.34:65.68; % H=5.62:5.31; % N=11.15:11.15; % Cl.=4.70:4.33.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₄₁H₄₁ClN₆O₄

[M+H]⁺ calculated: 717.2951

[M+H]⁺ measured: 717.2954

EXAMPLE 459

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1-ethyl-2-methyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the compound of Preparation 38″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=65.71; 65.29; % H=5.78:5.51; % N=10.95:10.95; % Cl.=4.62:4.39.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₄₂H₄₃ClN₆O₄

[M+H]⁺ calculated: 731.3107

[M+H]⁺ measured: 731.3109

EXAMPLE 460

5-(5-Chloro-2-{[(3R)-3-[3-(morpholin-4-yl)propyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-[1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl]-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 6′ inStep A, and the compound of Preparation 22″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=64.58:64.24; % H=6.05:5.88; % N=10.51:10.53; % Cl.=4.43:4.39.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₄₃H₃₇ClN₆O₅

[M+H]⁺ calculated: 763.3369

[M+H]⁺ measured: 763.3371

EXAMPLE 461

5-(5-Chloro-2-{[(3R)-3-[3-(morpholin-4-yl)propyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-1,2-dimethyl-N-phenyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 6′ inStep A, and the compound of Preparation 29″ in Step C, it beingunderstood that Step D is not carried out. The compound obtained isconverted into salt form and lyophilised as described in the generalprocess to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=67.44:66.68; % H=6.05:5.80; % N=10.97:10.95; % Cl.=4.63:4.57.

High-resolution mass spectrometry (ESI+/HR):

Empirical formula: C₄₃H₄₅ClN₆O₃

[M+H]⁺ calculated: 729.3314

[M+H]⁺ measured: 729.3316

EXAMPLE 462

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(5-methyl-1,2-oxazol-3-yl)-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the appropriate amine in Step C.

Elemental microanalysis: (%, theoretical:measured)

% C=67.10:66.64; % H=5.63:5.40; % N=10.30:10.24.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₃₈H₃₈ClN₅O₅

[M+H]⁺ calculated: 680.2634

[M+H]⁺ measured: 680.2637

EXAMPLE 463

N-(2-Ethoxypyrimidin-5-yl)-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 8 and the compound of Preparation 3′ inStep A, and the compound of to Preparation 39″ in Step C.

Elemental microanalysis: (%, theoretical:measured)

% C=68.17:67.52; % H=5.86:5.60; % N=11.92:11.43

EXAMPLE 464

5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-hydroxypyridin-2-yl)-1,2-dimethyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrole-3-carboxamidedihydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and the compound of Preparation 3′ inStep A, and the compound of Preparation 40″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

High-resolution mass spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₄₁H₄₀ClN₇O₄

[M+H]⁺ calculated: 730.2903

[M+H]⁺ measured: 730.2907

EXAMPLE 465

5-(4-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 29 and the compound of Preparation 3′ inStep A, and the compound of Preparation 18″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=65.34:64.81; % H=5.62:5.27; % N=11.15:10.95% Cl.=4.70:5.09.

High-resolution mass spectrometry (ESI+):

Empirical formula: C₄₁H₄₁ClN₆O₄

[M+H]⁺ calculated: 717.2951

[M+H]⁺ measured: 717.2952

EXAMPLE 466

5-(4-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxamidehydrochloride

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 29 and the compound of Preparation 3′ inStep A, and the compound of Preparation 1″ in Step C. The compoundobtained is converted into salt form and lyophilised as described in thegeneral process to obtain the title compound.

Elemental microanalysis: (%, theoretical:measured)

% C=66.77:62.82; % H=5.63:5.29; % N=11.74:11.75; % Cl.=5.01:5.23.

High-resolution muss spectrometry (ESI+/HR, ESI−/LR):

Empirical formula: C₃₈H₃₉ClN₆O₄

[M+H]⁺ calculated: 679.2794

[M+H]⁺ measured: 679.2796

EXAMPLE 467

5-(5-Chloro-2-{[3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-N-phenyl-1H-pyrrole-3-carboxamide

The title compound is obtained in accordance with the process of Example1 using the acid of Preparation 1 and 1,2,3,4-tetrahydroisoquinoline inStep A, and the compound of Preparation 2″ in Step C.

Elemental microanalysis: (%, theoretical:measured)

% C=72.97:72.93; % H=5.25:5.08; % N=7.29:7.34.

High-resolution mass spectrometry (ESI/FIA/HR and MS/MS):

Empirical formula: C₃₅H₃₀ClN₃O₃

[M+H]⁺ calculated: 576.2048

[M+H]⁺ measured: 576.2067

Pharmacological Study EXAMPLE A: INHIBITION OF BCL-2 BY THE FLUORESCENCEPOLARISATION TECHNIQUE

The fluorescence polarisation tests were carried out on microplates (384wells). The Bcl-2 protein, labelled (histag-Bcl-2 such that Bcl-2corresponds to the UniProtKB® primary accession number: P10415), at afinal concentration of 2.50×10⁻⁸ M, is mixed with a fluorescent peptide(Fluorescein-REIGAQLRRMADDLNAQY), at a final concentration of 1.00×10⁻⁸Min a buffer solution (Hepes 10 mM, NaCl 150 mM, Tween20 0.05%, pH 7.4),in the presence or absence of increasing concentrations of testcompounds. After incubation for 2 hours, the fluorescence polarisationis measured.

The results are expressed in IC₅₀ (the concentration of compound thatinhibits fluorescence polarisation by 50%) and are presented in Table 1below.

The results show that the compounds of the invention inhibit interactionbetween the Bcl-2 protein and the fluorescent peptide describedhereinbefore.

EXAMPLE B: IN VITRO CYTOTOXICITY

The cytotoxicity studies were carried out on the RS4;11 leukaemia tumourline.

The cells are distributed onto microplates and exposed to the testcompounds for 48 hours.

The cell viability is then quantified by a colorimetric assay, theMicroculture Tetrazolium Assay (Cancer Res., 1987, 47, 939-942).

The results are expressed in IC₅₀ (the concentration of compound thatinhibits cell viability by 50%) and are presented in Table 1 below.

The results show that the compounds of the invention are cytotoxic.

TABLE 1 IC₅₀ of Bcl-2 inhibition (fluorescence polarisation test) and ofcytotoxicity for RS4; 11 cells IC₅₀ (nM) Bcl-2 FP IC₅₀ (nM) MTT RS4; 11Example 1 5.0 33.6 Example 2 ND 1660 Example 3 24.6 94.9 Example 4 ND231 Example 5 21.2 44.8 Example 6 25.2 69 Example 7 25.6 90.6 Example 8ND 255 Example 9 22.4 87.5 Example 10 16.2 205 Example 11 14.2 202Example 12 5.5 39.6 Example 13 4.4 19.8 Example 14 3.7 8.23 Example 1511.1 69.4 Example 16 12.6 22.7 Example 17 8.0 75.2 Example 18 3.9 27.6Example 19 6.0 65.5 Example 20 4.9 164 Example 21 4.7 79.9 Example 226.6 45.7 Example 23 3.6 25.4 Example 24 6.2 79.1 Example 25 4.0 33.3Example 26 4.1 541 Example 27 5.2 93.4 Example 28 7.5 95.3 Example 296.6 47.5 Example 30 4.7 771 Example 31 7.2 89.3 Example 32 13.3 240Example 33 10.9 57.8 Example 34 8.2 47 Example 35 50.0 560 Example 3671.4 >600 Example 37 60.4 >600 Example 38 7.5 134 Example 39 7.2 19.7Example 40 64.4 431 Example 41 10.0 22.6 Example 42 5.2 4.36 Example 435.1 28.9 Example 44 3.0 5.41 Example 45 38.9 403 Example 46 76.6 >600Example 47 5.9 44.5 Example 48 4.4 14.9 Example 49 4.0 14.1 Example 505.9 33.1 Example 51 26.7 354 Example 52 28.9 433 Example 53 43.5 293Example 54 18.0 30.5 Example 55 209.6 >600 Example 56 75.0 >600 Example57 80.0 >600 Example 58 133.3 >600 Example 59 134.0 >600 Example 60 ND18.3 Example 61 4.5 37.8 Example 62 14.3 127 Example 63 5.1 11.2 Example65 21.9 113 Example 66 16.9 241 Example 67 12.5 98.6 Example 68 2.1 20.7Example 69 5.3 3.68 Example 70 8.5 63.5 Example 71 6.1 12.9 Example 727.7 43.6 Example 73 8 42.6 Example 74 4 45.4 Example 75 52.9 367 Example81 ND 249 Example 82 19.5 427 Example 88 15.9 69.6 Example 92 8.4 37.8Example 93 19.7 368 Example 94 8.6 104 Example 95 7 174 Example 96 13.5161 Example 97 19 98 Example 98 7.6 68.3 Example 99 6.4 108 Example 10022.9 193 Example 101 21.1 743 Example 102 2 6.51 Example 108 3.9 15.4Example 109 91.5 930 Example 110 8.5 39.5 Example 115 3.6 18.3 Example116 3.4 47.8 Example 122 3.4 82.4 Example 126 4.2 49.2 Example 127 5.3111 Example 129 18.1 275 Example 207 4.6 32.2 Example 209 7.4 25.4Example 210 8.8 47.2 Example 214 6.3 236 Example 230 5.1 18.3 Example358 14.8 165 Example 384 9.7 216 Example 385 5.7 28.7 Example 386 2.69.23 Example 387 20.6 243 Example 388 3.6 16.5 Example 389 14.7 208Example 390 21.2 173 Example 391 30.3 255 Example 392 3.8 11.4 Example393 2.1 1.95 Example 394 2.5 2.76 Example 395 3.5 7.57 Example 396 15.7116 Example 397 4.5 37.1 Example 398 3.9 13.4 Example 399 9.9 155Example 400 49 469 Example 401 8 24.3 Example 402 26.1 241 Example 40324.2 289 Example 404 24.4 85.5 Example 406 4.2 10.6 Example 407 20.6 150Example 408 5.4 4.46 Example 409 12.2 41.9 Example 410 9.9 61.6 Example411 5.5 32.8 Example 412 3.1 0.398 Example 413 3.1 9.43 Example 415 3.829.9 Example 416 2.9 42.5 Example 417 3 11 Example 418 10.1 159 Example419 2.8 15.8 Example 420 6.1 51.8 Example 421 2.5 3.73 Example 422 9.2101 Example 423 11.7 344 Example 424 13.6 102 Example 425 4.2 62 Example426 5.2 139 Example 427 2.2 23.3 Example 428 3.5 59.2 Example 429 3.1109 Example 430 19.9 328 Example 431 3 89 Example 432 3.4 76.6 Example433 2.6 48.2 Example 434 3.5 45.7 Example 435 14.9 441 Example 436 49.1338 Example 437 4.4 70.5 Example 438 11.3 379 Example 439 6.1 329Example 440 2.6 13.6 Example 441 3.5 132 Example 442 3 42.8 Example 443ND 57.9 Example 444 5.5 181 Example 445 2 19 Example 446 7.8 249 Example447 20 >600 Example 448 2.4 12.1 Example 449 1.7 11.9 Example 450 2.753.2 Example 451 2.9 102 Example 452 8.3 112 Example 453 6.9 99.9Example 454 6.5 158 Example 455 1.9 11.8 Example 456 2.7 80.6 Example457 ND 80.4 Example 458 10.5 197 Example 459 2.5 5.93 Example 460 2.822.9 Example 461 3.1 18.6 Example 462 13.3 368 Example 463 ND 40.8Example 464 36.6 723 Example 465 ND 50.6 Example 466 ND 493 Example 46719.2 188 ND: not determined

EXAMPLE C: INDUCTION OF CASPASE ACTIVITY IN VIVO

The ability of the compounds of the invention to activate caspase 3 isevaluated in a xenograft model of RS4;11 leukaemia cells.

1×10⁷ RS4;11 cells are grafted sub-cutaneously into immunosuppressedmice (SCID strain). 25 to 30 days after the graft, the animals aretreated orally with the various compounds. Sixteen hours aftertreatment, the tumour masses are recovered and lysed, and the caspase 3activity is measured in the tumour lysates.

This enzymatic measurement is carried out by assaying the appearance ofa fluorigenic to cleavage product (DEVDase activity, Promega). It isexpressed in the form of an activation factor corresponding to the ratiobetween the two caspase activities: the activity for the treated micedivided by the activity for the control mice.

The results obtained show that the compounds of the invention arecapable of inducing apoptosis in RS4;11 tumour cells in vivo.

EXAMPLE D: QUANTIFICATION OF THE CLEAVED FORM OF CASPASE 3 IN VIVO

The ability of the compounds of the invention to activate caspase 3 isevaluated in a xenograft model of RS4; II leukaemia cells.

1×10⁷ RS4;11 cells are grafted sub-cutaneously into immunosuppressedmice (SCID strain). 25 to 30 days after the graft, the animals aretreated orally with the various compounds. After treatment, the tumourmasses are recovered and lysed, and the cleaved (activated) form ofcaspase 3 is quantified in the tumour lysates.

The quantification is carried out using the “Meso Scale Discovery (MSD)ELISA platform” test, which specifically assays the cleaved form ofcaspase 3. It is expressed in the form of an activation factorcorresponding to the ratio between the quantity of cleaved caspase 3 inthe treated mice divided by the quantity of cleaved caspase 3 in thecontrol mice.

The results show that the compounds of the invention are capable ofinducing apoptosis in RS4;11 tumour cells in vivo.

TABLE 2 Caspase activation factors (cleaved caspase 3 MSD test in thetumours of treated mice versus control mice) in vivo, after treatment bythe oral route (exact doses in brackets) Time period after which thetumour Activation factor ± Compound tested is removed (T) SEM (versuscontrol) Example 25 2 hours 45.7 ± 2.0 (25 mg/kg) Example 28 2 hours72.3 ± 5.4 (12.5 mg/kg) Example 47 2 hours 12.3 ± 2.4 (25 mg/kg) Example61 2 hours 76.0 ± 5.2 (12.5 mg/kg) Example 67 2 hours 29.8 ± 4.0 (25mg/kg) Example 71 2 hours 46.8 ± 16.1 (25 mg/kg) Example 74 2 hours 24.5± 7.4 (12.5 mg/kg) Example 108 2 hours 22.6 ± 2.4 (12.5 mg/kg) Example230 2 hours 42.2 ± 9.3 (25 mg/kg) Example 386 2 hours 52.0 ± 8.6 (12.5mg/kg) Example 388 2 hours 85.7 ± 3.7 (25 mg/kg) Example 421 2 hours38.7 ± 10.7 (12.5 mg/kg) Example 449 2 hours 50.5 ± 3.4 (12.5 mg/kg)

EXAMPLE E: ANTI-TUMOUR ACTIVITY IN VIVO

The anti-tumour activity of the compounds of the invention is evaluatedin a xenograft model of RS4;11 leukaemia cells.

1×10⁷ RS4;11 cells are grafted sub-cutaneously into immunosuppressedmice (SCID strain). 25 to 30 days after the graft, when the tumour masshas reached about 150 mm³, the mice are treated orally with the variouscompounds in two different regimes (daily treatment for five days perweek for two weeks, or two treatments weekly for two weeks). The tumourmass is measured twice weekly from the start of treatment.

The results obtained accordingly show that the compounds of theinvention are capable of inducing significant tumour regression, whichcan be total, during the treatment period.

EXAMPLE F: PHARMACEUTICAL COMPOSITION: TABLETS

1000 tablets containing a dose of 5 mg of 5 g a compound selected fromExamples 1 to 467 Wheat starch 20 g Maize starch 20 g Lactose 30 gMagnesium stearate 2 g Silica 1 g Hydroxypropylcellulose 2 g

The invention claimed is:
 1. A process for the preparation of a compoundof formula (I′):

wherein: A₁ and A₂, each independently of the other, represent ahydrogen atom, a halogen atom, a linear or branched (C₁-C₆)polyhaloalkylgroup, a linear or branched (C₁-C₆)alkyl group or a cycloalkyl group; Trepresents a hydrogen atom, a linear or branched (C₁-C₆)alkyl groupoptionally substituted by from one to three halogen atoms, a(C₁-C₄)alkyl-NR₁R₂ group, or a (C₁-C₄)alkyl-OR₆ group; R₁ and R₂, eachindependently of the other, represent a hydrogen atom or a linear orbranched (C₁-C₆)alkyl group, or R₁ and R₂ form with the nitrogen atomcarrying them a heterocycloalkyl; R₃ represents a linear or branched(C₁-C₆)alkyl group, a linear or branched (C₂-C₆)alkenyl group, a linearor branched (C₂-C₆)alkynyl group, a cycloalkyl group, a(C₃-C₁₀)cycloalkyl-(C₁-C₆)alkyl group wherein the alkyl moiety is linearor branched, a heterocycloalkyl group, an aryl group or a heteroarylgroup, wherein one or more of the carbon atoms of the preceding groups,or of their possible substituents, may be deuterated; R₄ represents anaryl group, a heteroaryl group, a cycloalkyl group or a linear orbranched (C₁-C₆)alkyl group, wherein one or more of the carbon atoms ofthe preceding groups, or of their possible substituents, may bedeuterated; R₅ represents a hydrogen or halogen atom, a linear orbranched (C₁-C₆)alkyl group, or a linear or branched (C₁-C₆)alkoxygroup; R₆ represents a hydrogen atom or a linear or branched(C₁-C₆)alkyl group; R_(a) and R_(d), each independently of the others,represent a hydrogen atom, a linear or branched (C₁-C₆)alkyl group, alinear or branched (C₂-C₆)alkenyl group, a linear or branched(C₂-C₆)alkynyl group, an aryl group, a heteroaryl group, a halogen atom,a linear or branched (C₁-C₆)alkoxy group, a hydroxy group, a linear orbranched (C₁-C₆)polyhaloalkyl group, a trifluoromethoxy group, —NR₇R₇′,nitro, R₇—CO—(C₀-C₆)alkyl-, R₇—CO—NH—(C₀-C₆)alkyl-,NR₇R₇′—CO—(C₀-C₆)alkyl-, NR₇R₇′—CO—(C₀-C₆)alkyl-O—,R₇—SO₂—NH—(C₀-C₆)alkyl-, R₇—NH—CO—NH—(C₀-C₆)alkyl-,R₇—O—CO—NH—(C₀-C₆)alkyl-, a heterocycloalkyl group, or the substituentsof one of the pairs (R_(a),R_(b)), (R_(b), R_(c)), or (R_(c),R_(d)) formtogether with the carbon atoms carrying them a ring composed of from 5to 7 ring members, which ring may have from one to 2 hetero atomsselected from oxygen and sulphur, wherein one or more carbon atoms ofthe ring defined hereinbefore may be deuterated or substituted by fromone to 3 groups selected from halogen and linear or branched(C₁-C₆)alkyl; R_(b) and R_(c) are such that one represents a hydrogenand the other a group selected from R₇—CO—NH—(C₀-C₆)alkyl-,R₇—SO₂—NH—(C₀-C₆)alkyl-, R₇—NH—CO—NH—(C₀-C₆)alkyl- andR₇—O—CO—NH—(C₀-C₆)alkyl-, R₇ and R₇′, each independently of the other,represent a hydrogen atom, a linear or branched (C₁-C₆)alkyl group, alinear or branched (C₂-C₆)alkenyl group, a linear or branched(C₂-C₆)alkynyl group, an aryl group or a heteroaryl group, or R₇ andR₇′, together with the nitrogen atom carrying them, form a heterocyclecomposed of from 5 to 7 ring members; it being understood that: “aryl”means a phenyl, naphthyl, biphenyl or indenyl group, “heteroaryl” meansany mono- or bi-cyclic group composed of from 5 to 10 ring members,having at least one aromatic moiety and having from 1 to 4 hetero atomsselected from oxygen, sulphur and nitrogen , “cycloalkyl” means anymono- or bi-cyclic, non-aromatic, carbocyclic group having from 3 to 10ring members, “heterocycloalkyl” means any mono- or bi-cyclic,non-aromatic, condensed or spiro group composed of from 3 to 10 ringmembers and having from 1 to 3 hetero atoms selected from oxygen,sulphur, SO, SO₂ and nitrogen, wherein the aryl, heteroaryl, cycloalkyland heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyland alkoxy groups may be optionally substituted by from 1 to 3 groupsselected from optionally substituted, linear or branched (C₁-C₆)alkyl,(C₃-C₆)spiro, optionally substituted, linear or branched (C₁-C₆)alkoxy,(C₁-C₆)alkyl-S—, hydroxy, oxo (or N-oxide where appropriate), nitro,cyano, —COOR′, —OCOR′, NR′R″, linear or branched (C₁-C₆)polyhaloalkyl,trifluoromethoxy, (C₁-C₆)alkylsulphonyl, halogen, optionally substitutedaryl, heteroaryl, aryloxy, arylthio, cycloalkyl, heterocycloalkyloptionally substituted by one or more halogen atoms or alkyl groups,wherein R′ and R″, each independently of the other, represent a hydrogenatom or an optionally substituted, linear or branched (C₁-C₆)alkylgroup, or an enantiomer, a diastereoisomer, or an addition salt thereofwith a pharmaceutically acceptable acid or base, which process comprisessubjecting a compound of formula (II′):

wherein: Hal represents a halogen atom, X₁ and X₂ are such that onerepresents a (C₀-C₆)alkyl-NH₂ group while the other represents ahydrogen atom, which compound of formula (In is then subjected topeptide coupling with a compound of formula (VI):

to yield the compound of formula (III′):

which compound of formula (III′) is subjected to a Heck reaction, in anaqueous or organic medium, in the presence of a palladium catalyst, of abase, of a phosphine and of a compound of formula (IV′):

to form the compound of formula (V′):

which compound of formula (V′) is then subjected to an acylation orsulphonylation reaction to yield the compound of formula (P), whichcompound of formula (I′) may be purified according to a conventionalseparation technique, which is converted, if desired, into its additionsalts with a pharmaceutically acceptable acid or base and which isoptionally separated into its isomers according to a conventionalseparation technique, wherein, at any time considered appropriate in thecourse of the above-described process, certain groups of the reagents orintermediates of synthesis may be protected and then deprotectedaccording to the requirements of synthesis.
 2. The process according toclaim 1, wherein one of the groups R₃ or R₄ of the amine NHR₃R₄ issubstituted by a hydroxy function, which hydroxyl function is subjectedto a protection reaction prior to any coupling with the carboxylic acidformed from the compound of formula (VII), or with a corresponding acidderivative thereof, and wherein the resulting protected compound offormula (I′) undergoes a deprotection reaction and is then optionallyconverted into one of its addition salts with a pharmaceuticallyacceptable acid or base.
 3. The process according to claim 1, wherein A₁represents a hydrogen atom or a methyl group.
 4. The process accordingto claim 1, wherein A₂ represents a linear or branched (C₁-C₆)alkylgroup optionally substituted by a group selected from halogen, hydroxy,linear or branched (C₁-C₆)alkoxy, NR′R″ and morpholine.
 5. The processaccording to claim 1, wherein A₂ represents a linear or branched(C₁-C₆)polyhaloalkyl group or a cyclopropyl group.
 6. The processaccording to claim 1, wherein A₁ and A₂ both represent a methyl group.7. The process according to claim 1, wherein T represents methyl,aminomethyl, (morpholin-4-yl)methyl, (4-methylpiperazin-1-yl)methyl,2-(morpholin-4-yl)ethyl, [2-(morpholin-4-yl)ethoxy]methyl,hydroxymethyl, [2-(dimethylamino)ethoxy]methyl,hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl,1-oxa-6-azaspiro[3.3]hept-6-ylmethyl, 3-(morpholin-4-yl)propyl ortrifluoromethyl.
 8. The process according to claim 1, wherein R_(a), Rband R_(d) each represent a hydrogen atom and R_(c) represents a groupselected from R₇—CO—NH—(C₀-C₆)alkyl-, R₇—SO₂—NH—(C₀-C₆)alkyl-,R₇—NH—CO—NH—(C₀-C₆)alkyl- and R₇—O—CO—NH—(C₀-C₆)alkyl-.
 9. The processaccording to claim 1, wherein R₄ represents phenyl, 4-hydroxyphenyl,3-fluoro-4-hydroxyphenyl, 2-hydroxypyrimidine or 3-hydroxypyridine. 10.The process according to claim 1, wherein R₃ represents an aryl orheteroaryl group.
 11. The process according to claim 1, wherein R₃represents a group selected from methyl, phenyl, 1H-pyrazole, 1H-indole,1H-indazole, pyridine, pyrimidine, 1H-pyrrolo[2,3-b]pyridine,2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 1H-benzimidazole, 1H-pyrrole,1H-pyrrolo [2,3-c]pyridine, 1H-pyrrolo[3,2-b]pyridine,5H-pyrrolo[3,2-d]pyrimidine, thiophene, pyrazine,1H-pyrazolo[3,4-b]pyridine, 1,2-oxazole, and1H-pyrazolo[1,5-a]pyrimidine, those groups optionally having one or moresubstituents selected from halogen, linear or branched (C₁-C₆)alkyl,linear or branched (C₁-C₆)alkoxy, cyano, cyclopropyl, oxetane,tetrahydrofuran, —CO—O—CH₃, trideuteriomethyl, 2-(morpholin-4-yl)ethyland 2-(morpholin-4-yl)ethoxy.
 12. The process according to claim 11,wherein R₃ represents a linear or branched (C₁-C₆)alkyl or a heteroaryloptionally substituted by a linear or branched (C₁-C₆)alkyl, and R₄represents a 4-hydroxyphenyl group.